Infantile cold granules and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to granules for treating infantile common cold and a preparation method thereof. According to the present invention, the prescription research is performed aiming at the poor taste of the children's cold granules in the market, and the preparation method and the processing mode are adjusted, especially the whole volatile oil inclusion process is optimized; the problems of odor influence caused by volatile oil components such as pogostemon cablin and mint in the prescription and bitterness caused by isatis root and rehmannia are effectively solved.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to pediatric cold granules and a preparation method thereof. Background Art

[0002] Xiaoer Ganmao Granule is an over-the-counter medicine for children's colds. It is a commonly used antiviral medicine for pediatrics in clinical practice. Its prescription is composed of patchouli, chrysanthemum, forsythia, isatis leaf, isatis root, rehmannia root, radix lycopodii, radix dasycarpa, mint and gypsum, which has the functions of dispelling wind and relieving exterior symptoms, clearing away heat and detoxifying. In the prescription, isatis root is bitter and cold, gypsum is sweet and spicy, and when used as medicine, it is used as fine powder to produce the smell of the medicinal materials themselves; rehmannia root and radix dasycarpa are sweet and cold, chrysanthemum is sweet and bitter, and isatis leaf is bitter and cold. It is boiled in water and soaked in hot water, and the main extracts are compounds without irritating odor; radix dasycarpa is bitter, salty and cold, patchouli is spicy and slightly warm, and forsythia is bitter and slightly cold. It is boiled in water and used as medicine, mainly containing fatty acids and aldehydes, which are compounds with irritating odors; mint is spicy and cool, and will extract palmitic acid with a flavor. Therefore, although the pediatric cold granules taste sweet at first, they have a bitter aftertaste and are very irritating. Especially for children who are more sensitive to odors, the bad taste seriously affects the compliance and accuracy of pediatric patients in taking the medicine, thus restricting the market application of this product.

[0003] The pediatric cold granules that are currently on the market have been continuously produced and sold for many years, and have been recognized by the majority of users for their many excellent features such as convenient medication. However, since the formula contains several bitter herbs such as rhubarb and isatis root, the taste of the product is not ideal, which is difficult for children to accept; secondly, since the formula contains multiple volatile ingredients such as patchouli, mint, and forsythia, and the volatile oil is extracted and sprayed into the granules, the volatile oil is unstable and easily volatilized, and there is a sense of discomfort due to the bad smell during the taking process; in addition, although the granular granules are easier for children to accept, they have poor stability, and the rapid release of the drug efficacy leads to more frequent taking, which is extremely difficult for children who have difficulty feeding medicine. All of the above factors affect the clinical application of pediatric cold granules.

[0004] For example, the document "Study on the odor analysis and taste improvement of children's cold granules based on electronic tongue, GC-IMS technology and artificial sensory evaluation" reports that the taste of children's cold granules is improved by adding 2‰ sodium chloride for flavor correction, but because the added sodium chloride is salty, the compliance of this taste for children's medication is generally sweeter, and secondly, the stability of the volatile oil components in the prescription has not been solved, and the smell of the volatile components has not been covered, which also affects the product's taste. Another example is the children's cold granules disclosed in Chinese patent CN107308275A, which not only improves the dosage and quick effect by adding two medicinal flavors of oregano and mulberry leaves, but its volatile oil still adopts the spraying method, and the stability problem of the volatile components is not solved. Another example is the pediatric cold granules disclosed in Chinese patent CN104383117A, which adopt a specific ratio of the main drug to the auxiliary materials, which changes the taste of the product after dissolving in water, the difficulty in storage (caking, deterioration, discoloration, deliquescence) and the poor fluidity, but does not effectively improve the taste problem. In particular, the volatile oil is added by spraying after drying, which also poses the risk of unstable addition.

[0005] In summary, there are no technical reports in the art on improving the optimal taste of pediatric cold granules and the stability of the volatile oil of the active ingredient. Based on the target population of the product and considering the batch-to-batch differences in product quality, it is necessary to study the process of taste correction, odor masking and volatile oil addition, so as to improve the stability of the volatile oil and enhance the taste, which is beneficial to the efficacy of the product and the compliance of taking it. Summary of the invention

[0006] Therefore, the technical problem to be solved by the present invention is to provide a pediatric cold granule with better taste, so as to solve the problems of poor taste and unstable volatile oil of the pediatric cold granule in the prior art;

[0007] The second technical problem to be solved by the present invention is to provide a preparation method of the above-mentioned children's cold granules.

[0008] In order to solve the above technical problems, the preparation method of children's cold granules described in the present invention comprises the following steps:

[0009] (1) according to the raw material ingredients of the Xiaoer Ganmao granules, extract volatile oil from patchouli, mint, and forsythia, and collect the volatile oil and aqueous solution respectively;

[0010] (2) according to the raw material ingredients of the Xiaoganmao Granules, extract Rehmannia root, Psoralea corylifolia, Cortex Lycii, Flos Chrysanthemi, Folium Isatidis and part of Gypsum, and collect the extract;

[0011] (3) mixing the extract and the aqueous solution and concentrating the mixture into a clear paste;

[0012] (4) taking dextrin and / or β-cyclodextrin, adding water to the mixture and grinding it with a colloid mill, and then adding the volatile oil to carry out inclusion treatment to obtain a volatile oil inclusion compound;

[0013] (5) Take the clear paste, add the volatile oil inclusion compound, flavoring agent and essence to mix to obtain a mixed paste, and add crushed isatis root and remaining gypsum according to the raw material ingredients of the children's cold granules, mix and granulate to obtain the mixed paste.

[0014] Specifically, the preparation method of the children's cold granules is:

[0015] In the step (1), the step of extracting volatile oil comprises: steam distillation; and / or,

[0016] In the step (2), the extraction step includes: water extraction.

[0017] Specifically, in the method for preparing the pediatric cold granules, in the step (3), the mass ratio of the dextrin and / or β-cyclodextrin to water is 1:1-3.

[0018] Specifically, in the method for preparing the pediatric cold granules, in the step (4), the colloid mill includes a vertical colloid mill, a horizontal colloid mill, a split colloid mill or a closed colloid mill; preferably a split colloid mill.

[0019] Specifically, in the method for preparing the pediatric cold granules, in the step (4), the grinding time of the grinding step is 3-10 minutes.

[0020] Specifically, in the method for preparing the pediatric cold granules, in the step (4), the grinding time of the inclusion step is 10-15 minutes.

[0021] Specifically, in the method for preparing the pediatric cold granules, in the step (5), the flavoring agent includes at least one of sucralose, sucrose or sweetener NHDC; preferably sucralose.

[0022] Specifically, in the method for preparing the pediatric cold granules, in the step (5), the flavor includes mixed fruit flavor and / or red date flavor.

[0023] Specifically, the method for preparing the pediatric cold granules, in the step (5), further comprises the step of diluting the clear paste with water;

[0024] Preferably, the mass ratio of the clear paste to water is 10:3-5.

[0025] Specifically, the preparation method of the children's cold granules, the raw material composition of the children's cold granules is: 75 parts by weight of patchouli, 75 parts by weight of chrysanthemum, 75 parts by weight of forsythia, 125 parts by weight of scutellaria baicalensis, 75 parts by weight of isatis root, 75 parts by weight of rehmannia root, 75 parts by weight of lycium bark, 75 parts by weight of orchid, 50 parts by weight of mint, and 125 parts by weight of gypsum.

[0026] The invention also discloses children's cold granules prepared by the method.

[0027] The present invention conducts prescription research on the poor taste of the pediatric cold granules that have been marketed. By adjusting the preparation method and processing mode, especially optimizing the entire volatile oil inclusion process, the odor effect caused by volatile oil components such as patchouli and mint in the prescription and the bitterness caused by isatis root, rehmannia root, etc. are effectively solved. The medication taste evaluation of the pediatric cold granules of the present invention has stronger clinical significance and value, improves the palatability of the pediatric cold granules, improves the compliance of consumers, and the product is more suitable for children.

[0028] The preparation method of the children's cold granules of the present invention adopts an inclusion treatment method for volatile oil to effectively enhance its stability, and improves production efficiency by adjusting the production process, effectively solving the problem that the extracted volatile oil described in the preparation method of the legal standard is added after granulation and drying, which has the problem of volatile oil volatilization and poor stability in the preparation.

[0029] The preparation method of the children's cold granules of the present invention preferably uses β-cyclodextrin to include volatile oil, and adjusts the ratio of volatile oil to β-cyclodextrin, the ratio of β-cyclodextrin to water, and the inclusion time. Three factors are key factors affecting the inclusion of volatile oil. Patchouli alcohol, a representative component of volatile oil, is used as an investigation index. The batch variability of the content after inclusion is relatively small, while the direct addition method under the legal method has a large batch variability, and the content changes greatly during long-term storage.

[0030] According to the preparation method of the pediatric cold granules of the present invention, the flavor correction effect of the composite sweetener is significantly better than that of the single sweetener, among which sucralose+NHDC has the best flavor correction effect. Since the granules contain volatile oil inclusion compounds, an unpleasant odor will be volatilized when the granules are brewed, and therefore, flavors need to be added to cover up the unpleasant odor. According to prescription comparison, the taste of the granules with the addition of mixed fruit flavors and red dates flavors is better.

[0031] The preparation method of the children's cold granules of the present invention adopts a rapid inclusion method of a colloid mill to include volatile oil, and the process adopts an integrated one-step granulation method to granulate, so the production cost and efficiency are relatively high.

[0032] The preparation method of the children's cold granules of the present invention adopts the colloid mill grinding method for inclusion. The colloid mill is a commonly used fluid grinding mechanical equipment. Its basic working principle is to subject the fluid or semi-fluid material to strong shear force, friction force and high-frequency vibration through the high-speed relatively linked fixed teeth and moving teeth, so that it is effectively crushed, emulsified, homogenized and mixed, thereby obtaining a satisfactory finely processed product. The preparation method of the children's cold granules of the present invention adopts mechanical grinding such as colloid mill to prepare cyclodextrin inclusion compound, and its inclusion time is only 12 minutes. In addition, the aqueous solution and the inclusion compound are granulated at the same time. The volatile oil that is not included in the aqueous solution will also be mixed in the extract and granulated together, and the utilization rate of the volatile oil is also improved, which has the advantages of fast and simple processing. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] In order to make the content of the present invention more clearly understood, the present invention is further described in detail below according to specific embodiments of the present invention in conjunction with the accompanying drawings, wherein:

[0034] Figure 1 The present invention is a flow chart of the preparation of the children's cold granules;

[0035] Figure 2 For the control fingerprint (gas chromatography);

[0036] Figure 3 Comparison of gas phase fingerprints under different prescription processes of the present invention; from bottom to top, they are commercially available (legal process), process 5, process 1, process 2, process 4, and process 6;

[0037] Figure 4 This is a comparison chart of the gas phase fingerprint stability of the process of the present invention and the legal process; from bottom to top, it is commercially available (legal process, 0 month), commercially available (legal process, 12 months), process 5 (0 month), process 5 (12 months), commercially available (legal process, 24 months);

[0038] Figure 5 The ratio of volatile oil to β-cyclodextrin affects the results;

[0039] Figure 6 This is the result of the inclusion time investigation. DETAILED DESCRIPTION

[0040] Example 1

[0041] The ingredients are prepared according to the prescription of Children's Cold Granules. The specific composition of raw materials and auxiliary materials of the composition is shown in Table 1.

[0042] Table 1 Process prescription information

[0043] Serial number Name of raw materials Prescription dosage 1 Patchouli 75g 2 chrysanthemum 75g 3 Forsythia 75g 4 Big Leaf Green 125g 5 Isatis root 75g 6 Rehmannia root 75g 7 Lycium bark 75g 8 White Wei 75g 9 Mint 50g 10 plaster 125g 11 sucrose A 12 dextrin B 13 β-Cyclodextrin C 14 Sucralose D 15 essence E

[0044] In the above table, the total amount of sucrose A + sucralose D = 2 portions of pediatric cold granule paste; the total amount of dextrin B + β-cyclodextrin C = 1 portion of pediatric cold granule paste; the amount of flavor E = 50 μl of flavor per bag. The specific material selection and actual amount can be converted according to the actual amount of paste.

[0045] like Figure 1 In the process shown in the figure, the ingredients are prepared according to the prescription of children's cold granules in this embodiment. In order to improve the stability of the volatile oil in the granules, the extracted volatile oil is included and then granulated into a preparation. The specific preparation process includes:

[0046] According to the dosage prescribed in the pharmacopoeia, gypsum (part) and isatis root are crushed into fine powder; Rehmannia root, white mulberry, Chinese wolfberry bark and gypsum are mixed, decocted twice with water, the first time for 3 hours and the second time for 1 hour, the decoctions are combined and filtered; Chrysanthemum and isatis indigotica are hot-soaked twice, the first time for 2 hours and the second time for 1 hour, the extracts are combined and filtered; Patchouli, mint and forsythia are extracted with steam distillation to extract volatile oil, the aqueous solution is filtered, the filtrate is collected and combined with the above two liquids, and concentrated to a clear paste with a relative density of 1.30 to 1.35 (50°C);

[0047] Purified water twice the amount of β-cyclodextrin is mixed with β-cyclodextrin, added to the colloid mill, and ground for 5 minutes, then volatile oil is added for grinding and inclusion for 12 minutes to complete the inclusion process. When discharging, about 100 ml of water is used to wash away the inner wall and pipe residues twice; in this step, volatile oil (ml): β-cyclodextrin (g) = 1:9, β-cyclodextrin (g): water (ml) = 1:2;

[0048] The clear paste needs to be diluted with purified water. After adding purified water, add 40 kg (or adjust according to the proportion) to every 100 kg of the clear paste, stir and circulate for 15 to 20 minutes, and then heat the mixed slurry to 70°C. The relative density of the mixed slurry is 1.10 to 1.15 (50°C); then add the volatile oil inclusion compound, flavor, and sucralose to the mixed slurry, stir and circulate for 15 to 20 minutes to obtain a mixed paste, add the crushed isatis root and gypsum (powder) to mix, and then spray granulate.

[0049] Example 2

[0050] This embodiment provides a fingerprint method for determining the components of volatile oil and a method for determining the content of licorice alcohol, a representative component of volatile oil, to achieve a control means for investigating the reproducibility of the process.

[0051] Preparation of test sample: Take a commercially available sample of children's cold granules, mix it, take an appropriate amount, take 30g, weigh it accurately, and test it according to the volatile oil determination method (General Rule 2204). Add water from the upper end of the determination device until it fills the scale and overflows into the flask, then add 5ml of n-hexane, connect a reflux condenser, heat and keep it boiling slightly for 4 hours, cool it, and after the solution is clearly separated, take the n-hexane liquid, pass it through an anhydrous sodium sulfate column to remove water (take about 1g of anhydrous sodium sulfate and load it into a small column with an inner diameter of 1.2cm), put it in a 10ml volumetric flask, wash the inner wall of the volatile oil determination device with a small amount of n-hexane in several times, pass the n-hexane washing liquid through the anhydrous sodium sulfate column to remove water and add it into the same volumetric flask, add n-hexane to the scale, shake well, and obtain it.

[0052] Preparation of reference substance: Take an appropriate amount of Patchouli alcohol reference substance, weigh it accurately, and add n-hexane to make a solution containing 0.1 mg per 1 ml.

[0053] The reference solution and the test solution were subjected to gas chromatography analysis to obtain the GC fingerprint. The common peaks were determined based on the relative retention time with the reference solution. The characteristic peaks were determined using the standard solution as a reference. The GC fingerprint of the pediatric cold granules was established, and the content of patchouli alcohol was calculated by the external standard method.

[0054] The specific GC analysis conditions are:

[0055] Chromatographic conditions and system suitability test: A capillary column (length 30m, inner diameter 0.32mm, film thickness 0.25μm) with cross-linked 5% phenylmethyl polysiloxane as the stationary phase was used, and the temperature was programmed: initial temperature 60℃, maintained for 5min, increased to 140℃ at a rate of 2℃ per minute, increased to 240℃ at a rate of 10℃ per minute, and maintained for 20min. Inlet temperature 250℃; detector temperature (FID) 300℃; flow rate 1.5ml / min; carrier gas was nitrogen, split ratio 20:1. The theoretical plate number was not less than 1,000,000 based on the chloroquine peak.

[0056] Determination method: Accurately pipette 1 μl of reference solution and test solution respectively, inject into gas chromatograph, measure, and record the chromatogram for 75 minutes.

[0057] In this embodiment, the reference fingerprint (gas chromatography) is as shown in the attached Figure 2 As shown. It can be seen that the fingerprint of the test sample should present 24 common peaks, and the chromatographic peaks with the same retention time as the reference chromatographic peaks should appear, among which Peak 2: α-pinene, Peak 4: β-pinene, Peak 9: menthone, Peak 11: menthol, Peak 21 (S): patula alcohol.

[0058] According to the similarity evaluation system of Chinese medicine chromatographic fingerprint, the similarity between the test sample fingerprint and the control fingerprint shall not be less than 0.90.

[0059] Example 3

[0060] In this embodiment, the spectra of the children's cold granules under different processes are detected according to the detection method in Example 2.

[0061] In this embodiment, based on the preparation method in Example 1, the desired children's cold granules are prepared according to the following process settings 1-6, and spectrum detection is performed, and commercially available children's cold granules (i.e., the legal process) are used as a control. The specific process information is shown in Table 2 below, where the difference between process 1-6 and Example 1 is the type and amount of added flavoring agents and flavors.

[0062] Table 2 Summary of different process information

[0063]

[0064]

[0065] In this embodiment, the spectra under each process measured according to the method described in Example 2 are shown in the attached Figure 3 shown.

[0066] It can be seen that the fingerprint of the pediatric cold granules with added flavoring agents is compared with the gas phase fingerprint of the statutory process. There is no obvious difference between the spectra with the addition of sucralose and mixed fruit flavors and the statutory process. Other process differences come from the influence of the flavoring agent red date flavor and the sweetener NHDC. During the storage process, the volatile oil component of the statutory process gradually decreases, and the similarity is lower than 0.90 compared with 0 days. However, under the new process, the similarity can reach above 0.90, which proves that this method can identify the prescriptions of different flavoring agents and the stability of preparations.

[0067] In addition, the results of patchouli content are shown in Table 3. It can be seen that in the same batch of clear paste, the patchouli content of the legal process is lower, and the patchouli content of the volatile oil inclusion process is relatively stable and the content difference is small, indicating that the inclusion process is conducive to the retention of volatile oil.

[0068] Table 3 Results of patchouli content (calculated as patchouli alcohol)

[0069]

[0070]

[0071] Further, the spectra of the products in the screening process 5 of the present invention and the commercially available children's cold granules are shown in the attached Figure 4 shown.

[0072] It can be seen that the children's cold granule product under the screening preparation process of the present invention has higher stability.

[0073] Example 4

[0074] This embodiment optimizes the mouthfeel and flavor correction prescription.

[0075] (I) Screening of flavor correctors

[0076] This example is based on the preparation of the pediatric cold granules in Example 1, and different types of commonly used sweeteners and combinations thereof are added to screen the types and amounts of sweeteners. The experimental design and results are shown in Table 4 below.

[0077] Table 4 Experimental design of single sweeteners

[0078]

[0079] It can be seen from the above table that the use of single sweeteners did not achieve the best flavor correction effect. Further screening of compound flavor correctors was carried out. The experimental design and results are shown in Table 5.

[0080] Table 5 Compound sweeteners

[0081] Serial number Sweetener Type Sweetener dosage (mg / packet) Taste 1 NHDC+Neotame 15+6 Sweet 2 Stevioside + Neotame 10+2.5 Sweet 3 Sucralose + NHDC 20+10 Acceptable sweetness

[0082] It can be seen from the above table that the flavor-correcting effect of compound sweeteners is significantly better than that of single sweeteners, among which sucralose + NHDC has the best flavor-correcting effect. The ratio of the two will be further investigated in the future. The experimental design and results are shown in Table 6.

[0083] Table 6 Optimization of dosage of sucralose + NHDC

[0084]

[0085]

[0086] It can be seen from the above table that when the dosage of sucralose + NHDC is 10mg + 10mg or 10mg + 20mg, the flavor correction effect is the best.

[0087] (II) Fragrance screening

[0088] Since the granules contain volatile oil inclusion compounds, an unpleasant odor will be volatilized when the granules are brewed, and therefore flavors need to be added to cover up the unpleasant odor. This embodiment screens and optimizes suitable flavors.

[0089] This example is based on the preparation of the children's cold granules in Example 1, and different flavors are added for screening.

[0090] (1) Selection of fruit flavor types and dosage

[0091] Different types of fruit flavors and their combinations were added to the pediatric cold granules to screen the types and amounts of flavors. The experimental design and results are shown in Table 7 below.

[0092] Table 7 Fruit flavor screening

[0093]

[0094]

[0095] (2) Selection of fruit flavor types and dosage

[0096] Different types of beverage flavors and their combinations were added to the pediatric cold granules to screen the types and amounts of flavors. The experimental design and results are shown in Table 8 below.

[0097] Table 8 Beverage flavor screening

[0098]

[0099] (3) Selection of flower flavor essence types and dosage

[0100] Different types of flower-flavored essences and their combinations were added to the pediatric cold granules to screen the types and dosages of the essences. The experimental design and results are shown in Table 9 below.

[0101] Table 9 Screening of floral fragrance essence

[0102]

[0103] (4) Selection of flavors and dosages for other ingredients

[0104] Different types of food flavors and their combinations were added to the pediatric cold granules to screen the types and amounts of flavors. The experimental design and results are shown in Table 10 below.

[0105] Table 10 Screening of other food flavors

[0106]

[0107]

[0108] It can be seen that among the screening of flavors of different types and dosages, only red date flavor and mixed fruit flavor have a certain masking effect, and can be used as a prescription optimization flavor for screening complex flavor correction.

[0109] Example 5

[0110] In this example, based on the preparation method of Example 1, the flavor correction system selected in the above Example 4 is further used to prepare the children's cold granules.

[0111] Sample preparation

[0112] Sample No. 0: Pediatric cold granules without flavor correction, processed according to the original process;

[0113] Sample No. 1: Sweet orange flavor (sucralose + NHDC + sweet orange flavor essence): add 20 mg sucralose, 18 mg NHDC, and 160 μl sweet orange flavor essence to a pack (6 g) of children's cold granules;

[0114] Sample No. 2: Strawberry flavor (sucralose + NHDC + strawberry flavor + citric acid + salt): add 20 mg sucralose, 20 mg NHDC, 8 mg citric acid, 5 mg salt, and 120 μl strawberry flavor to a pack (6 g) of children's cold granules;

[0115] Sample No. 3: Blueberry flavor (sucralose + NHDC + blueberry flavor essence + citric acid): add 20 mg sucralose, 18 mg NHDC, 3 mg citric acid, and 120 μl blueberry flavor essence to a pack (6 g) of children's cold granules;

[0116] Sample No. 4: Mixed Fruit Flavor (Sucralose + NHDC + Salt + Mixed Fruit Flavor Essence): Add 20 mg sucralose, 18 mg NHDC, 5 mg NaCL, and 140 μl mixed fruit flavor essence to a pack (6 g) of Children's Cold Granules;

[0117] Sample No. 5: Pineapple flavor (sucralose + NHDC + California pineapple flavor): Add 20 mg sucralose, 18 mg NHDC, and 140 μl California pineapple flavor to a pack (6 g) of children's cold granules.

[0118] Evaluation results

[0119] After taste research, feedback showed that sample No. 2 had the best smell and sweetness, but since the volatile oil in the sample particles provided this time was sprayed, the smell was weak, so the fruit aroma used could cover the volatile oil smell. In the particles received later, the volatile oil was encapsulated by cyclodextrin, and there was a strong volatile oil smell when brewing, and the light fruit aroma could not cover the volatile oil smell.

[0120] Example 5

[0121] In this embodiment, based on the preparation method of embodiment 1, children's cold granules are prepared further based on the flavor correction system selected in the aforementioned embodiment 4.

[0122] Sample preparation

[0123] Sample No. 0: Pediatric cold granules without flavor correction, processed according to the original process;

[0124] Sample No. 1: Mixed Fruit Flavor + Red Date Flavor (Sucralose + NHDC + Mixed Fruit Flavor + Forsythia suspensa Masking Agent + Red Date Flavor): Add 15mg sucralose, 15mg NHDC, 400μl mixed fruit flavor, 100μl Forsythia suspensa masking agent, and 200μl red date flavor to a pack (6g) of Children's Cold Granules;

[0125] Sample No. 2: Mixed Fruit Flavor (Sucralose + NHDC + Mixed Fruit Flavor Essence + Forsythia suspensa masking agent): Add 15 mg sucralose, 15 mg NHDC, 400 μl mixed fruit flavor essence, and 100 μl Forsythia suspensa masking agent to a pack (6 g) of Children's Cold Granules.

[0126] Evaluation results

[0127] The taste survey showed that the unflavored sample No. 0 had the best smell and sweetness. Since the granules used this time contained some sweeteners, and the taste evaluators did not consider children's tolerance and preference for sweetness, they believed that samples No. 1 and No. 2 were too sweet. In addition, due to the large amount of mixed fruit essence used, there was a more obvious alcohol smell when brewing.

[0128] Example 6

[0129] In this embodiment, based on the preparation method of embodiment 1, children's cold granules are prepared further based on the flavor correction system selected in the aforementioned embodiment 4.

[0130] Sample preparation

[0131] Sample No. 0: Pediatric cold granules without flavor correction, processed according to the original process;

[0132] Sample No. 1: Mixed Fruit Flavor + Red Date Flavor (Mixed Fruit Flavor Essence + Red Date Flavor Essence): Add 300μl of mixed fruit flavor essence and 200μl of red date flavor essence to a pack (6g) of children's cold granules;

[0133] Sample No. 2: Mixed Fruit Flavor (Mixed Fruit Flavor Essence + Forsythia suspensa Screening Agent): Add 300μl of mixed fruit flavor essence and 100μl of Forsythia suspensa screener to a pack (6g) of children's cold granules.

[0134] Evaluation results

[0135] The taste survey results showed that sample No. 1 had the best smell. According to the evaluation results of the second batch of samples, no sweetener was added to this sample, so the children's evaluation results showed that the sweetness of the three samples was not enough. The flavors used in samples No. 1 and No. 2 can mask the pungent smell of volatile oils to a certain extent, and the number of people who chose sample No. 1 is slightly more than that of sample No. 2.

[0136] Example 7

[0137] This embodiment further optimizes the flavor correction system based on the solutions and effects in the aforementioned embodiments 4-6.

[0138] Based on the results of the cost structure, NHDC was removed, and the flavoring agents sucralose, mixed fruit flavor, and red date flavor were adjusted again. An orthogonal experimental combination was conducted with three flavoring agents as three factors and three levels of dosage, as shown in Tables 11-12 below.

[0139] Table 11 Orthogonal factor variable table

[0140] name Sucralose (mg / bag) Fruity flavor essence (μl / bag) Red date flavor essence (μl / bag) 1 15 150 150 2 10 100 100 3 5 50 50

[0141] Table 12 Orthogonal experiment table

[0142]

[0143]

[0144] For the 9 samples that used the method of adjusting the proportion of flavoring agents, considering that the increased cost is not higher than that of process 3, after taste testing, it is suggested that the sweetness of the taste can be reduced on the basis of process 2, and the requirement for the smell does not need to be too strong. Therefore, considering the cost again, three more process samples were prepared for taste research, and process 5 was determined to be the best.

[0145] Example 8

[0146] In this embodiment, based on the aforementioned flavor correction system, the volatile oil inclusion formula is further adjusted.

[0147] At present, the process parameters of the inclusion process include drying temperature, colloid mill load, the ratio of volatile oil and β-cyclodextrin, and inclusion time. A single factor investigation is first carried out, and then an orthogonal test is performed to optimize the process parameters.

[0148] The results of the drying temperature investigation are shown in Table 13 below.

[0149] Table 13 Drying temperature investigation

[0150] Drying temperature(℃) Oil content of inclusion compound (mg / g) 60 0.088 70 0.087 80 0.088

[0151] From the table above, we can see that after the cyclodextrin inclusion compound is dried in an oven at 60℃, 70℃, and 80℃ for 22 hours, the volatile oil content is not much different. Therefore, the drying temperature of the inclusion compound is determined to be 80℃. It is used for the determination of orthogonal test indicators.

[0152] The load investigation results of the colloid mill are shown in Table 14 below.

[0153] Table 14 Load investigation of colloid mill

[0154] Load(Kg) Oil content of inclusion compound (mg / g) 1.5 0.086 2.3 0.086 3.0 0.085

[0155] From the table above, we can see that when three loading amounts of high, medium and low are selected and the volatile oil inclusion is carried out with the same ratio and inclusion conditions, the volatile oil content of the inclusion compound is not much different after drying in an oven at 80°C for 22 hours, which indicates that the effect of loading amount on the inclusion effect is negligible.

[0156] The results of the investigation on the ratio of volatile oil and β-cyclodextrin are shown in the attached Figure 5 It can be seen that when the ratio of volatile oil to β-CD is below 1:8, β-CD is in a state of deficiency; when the ratio of volatile oil to β-CD is 1:11, β-CD is excessive relative to volatile oil, so the three levels of 1:8, 1:9, and 1:10 are selected to be included in the orthogonal experiment for investigation.

[0157] The results of the inclusion time investigation are attached. Figure 6 It can be seen that the inclusion process occurs very quickly, and the oil content of the inclusion complex tends to be stable after 10 minutes. Therefore, three levels of 8, 10, and 12 minutes were selected for investigation in the orthogonal experiment.

[0158] Orthogonal test

[0159] According to the determined parameters and indicators, as well as the results of the single factor investigation, the factors and indicators finally selected are shown in the table below. Assuming that there is no interaction between the factors, the orthogonal table L9 (3 4 ) to arrange the experiment. The optimal solution was selected based on the inclusion rate of volatile oil as the evaluation index. The specific information is shown in Tables 15-16 below.

[0160] Table 15 Volatile oil inclusion factor level table

[0161]

[0162] Table 16 Volatile oil inclusion factor level table

[0163] Test No. A empty column B C Trial plan 1 1 1 1 1 <![CDATA[A 1 B 1 C 1 ]]> 2 1 2 2 2 <![CDATA[A 1 B 2 C 2 ]]> 3 1 3 3 3 <![CDATA[A 1 B 3 C 3 ]]> 4 2 1 2 3 <![CDATA[A 2 B 2 C 3 ]]> 5 2 2 3 1 <![CDATA[A 2 B 3 C 1 ]]> 6 2 3 1 2 <![CDATA[A 2 B 1 C 2 ]]> 7 3 1 3 2 <![CDATA[A 3 B 3 C 2 ]]> 8 3 2 1 3 <![CDATA[A 3 B 1 C 3 ]]> 9 3 3 2 1 <![CDATA[A 3 B 2 C 1 ]]>

[0164] According to the above 9 test schemes, β-cyclodextrin (β-CD) was weighed (according to the level in column A, the amount of volatile oil added was 100 ml), placed in an appropriate container, added with water (according to the level in column B), stirred evenly, poured into a colloid mill and ground for 5 minutes, slowly poured in volatile oil, ground for a certain time (according to the level in column C), dried in an oven at 80°C for the same length of time until all samples were dry, ground, determined the volatile oil content and inclusion complex yield, calculated the range, and the results are listed in the following Tables 17-18.

[0165] Table 17 Volatile oil inclusion process optimization test plan and result analysis (inclusion oil content)

[0166]

[0167] Table 18 Volatile oil inclusion process optimization test plan and result analysis (inclusion yield)

[0168]

[0169]

[0170] Range Analysis

[0171] ① Taking the inclusion compound oil content as an indicator for analysis, the range of each factor is: A = 0.018; B = 0.002; C = 0.001; error = 0.001. The level of each factor has the greatest impact on the test results for volatile oil (ml): β-cyclodextrin (g), and the other two indicators (β-cyclodextrin: water and inclusion time) have little effect on the results, and the range of the error column is also small, indicating that the interaction between the factors can be ignored.

[0172] From the changing trends of the three factors, it can be seen that when the ratio of volatile oil (ml): β-cyclodextrin (g) is 1:8, the oil content of the inclusion complex is higher than the other levels; when the ratio of β-cyclodextrin: water is 1:1.8 and 1:1.6, the average value is higher than 1:2.0; the inclusion time does not change much within 8 to 12 minutes, which is similar to the results of the previous single-factor investigation.

[0173] ② Taking the inclusion compound yield as an indicator for analysis, the ranges of each factor are: A = 4.370; B = 3.076; C = 4.380; Error = 0.644. The influence of each factor level on the test results is in the order of inclusion time, volatile oil (ml): β-cyclodextrin (g), β-cyclodextrin: water, and the range of the error column is also small, indicating that the interaction between the factors can be ignored.

[0174] In actual operation, it was found that since the split colloid mill of the testing machine is an open system, a certain amount of sample will splash out during the grinding process, which will have a certain impact on the calculation of the inclusion compound yield. Based on experience, there are two assumptions: the longer the time, the greater the loss; the smaller the load, the greater the relative loss. It can also be seen from the range analysis that the inclusion time has the greatest impact on the results, and the trend also verifies the above assumptions. Considering that the inclusion compound yield of 9 tests is basically stable at around 80%, this experiment ignores the inclusion compound yield indicator and only considers the inclusion compound oil content as an indicator to screen the inclusion process.

[0175] Volatile oil inclusion compound addition method

[0176] Volatile oil inclusion complex can be added in two ways: ① granulate as a solid material after drying, ② add to the clear paste after preparation of the inclusion complex and add as a binder. Weigh 800g of β-cyclodextrin (β-CD), place in an appropriate container, add 1280g of water, stir evenly, pour into a colloid mill and grind for 5 minutes, slowly pour in 100ml of volatile oil, grind for a certain time of 12 minutes, divide into two parts, one part is dried in an oven at 80℃ for the same length of time until all samples are dry, grind, and one part is not dried and directly added to the clear paste, granulated separately, and the content of patchouli alcohol in the granules is determined, see Table 19 below for details.

[0177] Table 19 Patchouli alcohol content

[0178] batch number Patchouli alcohol content (mg / bag) 20170417-1(Inclusion compound drying) 0.14 20170417-2 (Inclusion compound is not dried) 0.22

[0179] Study on thermal stability of volatile oil inclusion complex

[0180] Weigh 800g of β-cyclodextrin (β-CD), place it in a suitable container, add 1280g of water, stir evenly, pour it into a colloid mill and grind for 5 minutes, slowly pour in 100ml of volatile oil, grind for a certain time of 12 minutes, dry it in an oven at 80℃ for the same period of time until all the samples are dry, grind it, and measure its oil content to be 0.114ml / g, and divide it into three portions, accurately weigh 30g of each portion, heat it in a drying oven at 90℃, 100℃, and 110℃ for 3 hours, transfer it to a volatile oil extractor, extract the volatile oil using volatile oil determination method A, measure the volume of the volatile oil, and the results are shown in Table 20 below.

[0181] Table 20 Volume of volatile oil

[0182] Temperature(℃) Oil content of inclusion compound (ml / g) 90 0.098 100 0.085 110 0.073

[0183] Volatile oil preservation rate

[0184] The preservation rates of volatile oil under different volatile oil adding methods were compared.

[0185] ① After granulation, the volatile oil was directly sprayed into the sample of granules and placed at room temperature for 12 months, and the volatile oil preservation rate was about 20%; the content of patchouli alcohol was 0.04 mg / bag.

[0186] ② For the samples granulated with volatile oil added to the fluid paste, no volatile oil (patchouli alcohol) could be detected in the granules when they were examined at the end of their validity period of 3 years;

[0187] ③ The volatile oil was encapsulated with β-cyclodextrin and granulated. The volatile oil preservation rate was about 80% at 0 month. After being placed under accelerated conditions (40℃±2℃, RH75%±5%) for 3 months, the volatile oil preservation rate dropped to 60%. After being placed under accelerated conditions for 6 months, the volatile oil preservation rate was still 60%. After being placed under long-term conditions (25℃±2℃, RH60%±5%) for 24 months, the volatile oil preservation rate was about 75%, and the content of patchouli alcohol was 0.17mg / bag.

[0188] From the above results, it can be seen that the preservation rate of volatile oil is the highest after being included in β-cyclodextrin, while it is more likely to be lost after being added in other ways.

[0189] Example 9

[0190] This embodiment is based on the solution of embodiment 1 and is compared with the prior art solution.

[0191] For example, the pediatric cold granules and preparation method disclosed in Chinese patent CN 111905024A differ from the present application mainly in the inclusion method of volatile oil and the granulation method.

[0192] For example, the preparation method of children's cold granules disclosed in Chinese patent CN 111905024A adopts the following steps: after volatile oil extraction and water extraction of active ingredients, β-cyclodextrin 5-7 times the amount of volatile oil is weighed into a reactor, an appropriate amount of purified water is added, and the mixture is heated in a boiling water bath until it is completely dissolved, the temperature is lowered, and volatile oil dissolved in one time of ethanol is added. After stirring for 2 hours, the mixture is allowed to stand for 24 hours, and filtered to obtain volatile oil β-cyclodextrin inclusion compound; the sterilized powder, volatile oil β-cyclodextrin inclusion compound, twice the amount of sucrose powder in a clear paste, and one time the amount of dextrin in a clear paste are taken and placed in a trough mixer for mixing to form a soft material, which is then dried, granulated, and sieved.

[0193] It can be seen that although this scheme has included the volatile oil, the inclusion method is a conventional stirring inclusion method. This scheme not only has a long inclusion time, but also requires standing for 24 hours before filtering the solid obtained and wet granulating it with the extract.

[0194] The scheme in Example 1 of the present invention adopts a colloid mill grinding method for inclusion, in which β-cyclodextrin is evenly ground with several times water, and then volatile oil is added and ground and mixed into a paste to obtain an inclusion compound. The inclusion time is only 12 minutes, and the aqueous solution and the inclusion compound are granulated at the same time, so that the volatile oil not included in the aqueous solution will also be mixed in the extract and granulated together, and the utilization rate of the volatile oil is also improved.

[0195] In addition, in this comparative example, the inclusion compound is solid after filtration, and there is a risk of loss of volatile oil during granulation after addition.

[0196] Example 10

[0197] This example further compares the differences in the content of tricholol in different volatile oil inclusion compounds under waterproofing according to the scheme in Example 1.

[0198] Based on the scheme of Example 1, 800 g of β-cyclodextrin (β-CD) was weighed and placed in a suitable container. 1280 g of water was added and stirred evenly. The mixture was poured into a colloid mill and ground for 5 minutes. 100 ml of volatile oil was slowly poured in and ground for a certain time of 12 minutes. The mixture was divided into two portions:

[0199] One portion was dried in an oven at 80°C for the same period of time until all the samples were dried and ground (i.e., granulated as a solid material after drying);

[0200] One part is added directly to the clear paste without drying, and granulated separately (that is, after preparing the inclusion compound, it is added to the clear paste as a binder);

[0201] The content of trichol in the granules was determined, see Table 21 below for details.

[0202] Table 21 Patchouli alcohol content

[0203] batch number Patchouli alcohol content (mg / bag) Method 1: Inclusion compound drying 0.14 Method 2: The inclusion compound is not dried 0.22

[0204] It can be seen that the preparation method of the children's cold granules of the present invention adopts the method of inclusion treatment for volatile oil, effectively enhancing its stability, and improving production efficiency by adjusting the production process. Obviously, the above embodiments are only examples for clear explanation, and are not limitations on the implementation methods. For ordinary technicians in the field, other different forms of changes or variations can be made on the basis of the above description. It is not necessary and impossible to list all the implementation methods here. And the obvious changes or variations derived from this are still within the scope of protection created by the present invention.

Claims

1. A method for preparing pediatric cold granules, characterized in that: The steps include: (1) according to the raw material ingredients of the Xiaoer Ganmao granules, extract volatile oil from patchouli, mint, and forsythia, and collect the volatile oil and aqueous solution respectively; (2) according to the raw material ingredients of the Xiaoganmao Granules, extract Rehmannia root, Psoralea corylifolia, Cortex Lycii, Flos Chrysanthemi, Folium Isatidis and part of Gypsum, and collect the extract; (3) mixing the extract and the aqueous solution and concentrating the mixture into a clear paste; (4) taking dextrin and / or β-cyclodextrin, adding water to the mixture and grinding the mixture with a colloid mill, and then adding the volatile oil to the mixture for inclusion treatment to obtain a volatile oil inclusion compound; (5) Take the clear paste, add the volatile oil inclusion compound, flavoring agent and essence to mix to obtain a mixed paste, and add crushed isatis root and remaining gypsum according to the raw material ingredients of the children's cold granules, mix and granulate to obtain the mixed paste.

2. The method for preparing the children's cold granules according to claim 1, characterized in that: In the step (1), the step of extracting volatile oil comprises steam distillation; and / or, In the step (2), the extraction step comprises water extraction.

3. The method for preparing the children's cold granules according to claim 1 or 2, characterized in that: In the step (4), the mass ratio of the dextrin and / or β-cyclodextrin to water is 1:1-3.

4. The method for preparing the children's cold granules according to any one of claims 1 to 3, characterized in that: In the step (4), the colloid mill includes a vertical colloid mill, a horizontal colloid mill, a split colloid mill or a closed colloid mill; preferably a split colloid mill.

5. The method for preparing the children's cold granules according to any one of claims 1 to 4, characterized in that: In the step (4): The grinding time of the grinding step is 3-10 min; and / or, The grinding time of the inclusion step is 10-15 min.

6. The method for preparing the children's cold granules according to any one of claims 1 to 5, characterized in that: In the step (5), the flavoring agent includes at least one of sucralose, sucrose or sweetener NHDC; preferably sucralose.

7. The method for preparing the children's cold granules according to any one of claims 1 to 6, characterized in that: In the step (5), the flavor includes mixed fruit flavor and / or red date flavor.

8. The method for preparing the children's cold granules according to any one of claims 1 to 7, characterized in that: The step (5) further includes the step of diluting the clear paste by adding water; Preferably, the mass ratio of the clear paste to water is 10:3-5.

9. The method for preparing the children's cold granules according to any one of claims 1 to 8, characterized in that: The raw material composition of the children's cold granules is: 75 parts by weight of patchouli, 75 parts by weight of chrysanthemum, 75 parts by weight of forsythia, 125 parts by weight of scutellaria baicalensis, 75 parts by weight of isatis root, 75 parts by weight of rehmannia root, 75 parts by weight of lycium bark, 75 parts by weight of orchid, 50 parts by weight of mint, and 125 parts by weight of gypsum.

10. A pediatric cold granule prepared by the method according to any one of claims 1 to 9.

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