Traditional Chinese medicine granule mimetic agent for cough after respiratory tract infection and preparation method of traditional Chinese medicine granule mimetic agent

Abstract

The invention discloses a composition for preparing a traditional Chinese medicine granule mimetic agent, which is prepared from the following components in percentage by mass: 96.30 to 99.12 percent of filling agent, 0.08 to 0.7 percent of coloring agent, 0.3 to 1.0 percent of flavoring agent and 0.5 to 2 percent of suspending aid, and the sum of the mass percent of the components is 100 percent. Wherein the filler is selected from dextrin and / or soluble starch; the coloring agent is selected from one or more of indigo pigment, brilliant blue pigment, sunset yellow pigment, lemon yellow pigment and carmine; the flavoring agent comprises a bitter agent, a sweetening agent, an acidulant and essence; the suspending aid is sodium carboxymethyl cellulose; the traditional Chinese medicine granules are radix scutellariae, scalded semen armeniacae amarae, platycodon grandiflorum, liquorice, radix peucedani and radix bupleuri. The invention also provides an apricot-baical skullcap root cough-sensitive granule simulation agent and a preparation method thereof. The mimetic agent provided by the invention has high similarity with new traditional Chinese medicine class I new medicine Xiangqin cough-sensitive granules, can effectively prevent bias or blurring in a clinical test, and ensures smooth development of the clinical test.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmacy and Chinese medicine preparation, and particularly relates to a Chinese medicine granule simulation agent and a preparation method thereof. Background Art

[0002] Double-blind design is widely used in randomized controlled trials to eliminate potential non-drug effects. The latest version of the Good Clinical Practice (GCP) clearly states that the test drug should be able to maintain a blind state in a blinded trial. Simulator (placebo) refers to a preparation or dosage form that does not contain any component that affects the observed physiological or pathological phenomenon, and is as completely identical as possible with the test drug in terms of appearance, color, smell, taste, etc. It is one of the important factors affecting drug clinical research, and its simulation effect determines whether there is a possibility of breaking the blind during the implementation of the drug clinical trial, thereby affecting the quality of the entire clinical trial and the objectivity and accuracy of the drug efficacy evaluation. The preparation of Chinese medicine preparations has certain difficulty due to their special smell and taste. The Classification and Application Materials Requirements for Chinese Medicine Registration proposes that the sponsor needs to provide a comparative study of the nature and taste of placebo and test samples, and explains the consistency of placebo and test samples in terms of appearance, size, color, weight, taste and smell. Therefore, Chinese medicine simulator (placebo) is one of the issues that attract much attention in the current clinical trials of new Chinese medicines.

[0003] Chinese medicine granules generally refer to dry granular preparations with a certain particle size made by mixing extracts of Chinese medicinal materials and suitable excipients, which are taken orally with water. Each Chinese medicine granule has a specific color and / or smell due to the different prescription medicinal materials. The simulant of Chinese medicine granules must be similar to the smell, taste and color of the test drug in both solid and liquid states. Therefore, compared with other solid preparations (such as tablets and capsules), the preparation of simulants of Chinese medicine granules is more difficult.

[0004] The compositions of the Chinese medicine granule simulation agents recorded in the prior art are generally divided into two categories:

[0005] 1) A small amount of Chinese medicine granules and excipients; such as the Chinese invention patent application "Guanxinfang Placebo" with publication number CN102133408A (publication date July 27, 2011), the Chinese invention patent application "Chinese medicine placebo and its preparation process and evaluation method" with publication number CN103110962A (publication date May 22, 2013), and the Chinese invention patent application "Baihu Ginseng Granule Placebo and Its Preparation Method" with publication number CN112089850A (publication date December 18, 2020).

[0006] This type of simulator is closer to the therapeutic preparation in terms of smell and taste because of the addition of Chinese medicine granules. However, due to the presence of Chinese medicine, the active ingredients in it may affect the physiological or pathological phenomena of the subjects and reduce the simulation effect of the simulator.

[0007] 2) Only excipients, such as excipients, colorants (colorants) and flavoring agents, etc.; such as the Chinese invention patent application "A method for preparing a Chinese medicine formula granule placebo" with publication number CN113876717A (publication date January 4, 2022), the Chinese patent "A placebo and its application" with announcement number CN112076323B (announcement date May 9, 2023), and the Chinese invention patent application "A Chinese medicine preparation placebo for treating knee synovitis and its preparation method" with publication number CN102631688A (publication date August 15, 2012).

[0008] This type of simulator basically does not contain chemical components from traditional Chinese medicine; however, it is more difficult to achieve similarity with the test preparation in solid and liquid states.

[0009] Xingqin Ganke Granules, a new Chinese medicine of category 1.1, is currently undergoing a randomized controlled dose-exploratory Phase II clinical trial to evaluate the efficacy and safety of treating cough after a cold (wind-heat lurking in the lungs). Xingqin Ganke Granules are composed of six medicinal materials: Scutellaria baicalensis, boiled bitter almonds, Platycodon grandiflorum, Licorice, Peucedanum chinense and Bupleurum chinense. They have the functions of dispelling wind and heat, promoting lung function and relieving cough. They are used to treat cough after a cold (upper respiratory tract infection) (wind-heat lurking in the lungs). Symptoms include cough, dry cough without or with little sputum, itchy throat, coughing when it itches, or choking coughs, shortness of breath, sudden or aggravated by factors such as cold, heat, and peculiar smell, and coughing is often severe when lying down at night and waking up in the morning, with repeated attacks, red tongue with thin yellow fur, and stringy pulse. The Phase II clinical trial of Xingqin Ganke Granules adopts a multicenter, randomized, double-blind, dose-exploring, and sham parallel control superiority design. The sham is one of the important factors affecting clinical research. Therefore, it is necessary to design and prepare a simulator that is as close as possible to the Xingqin Ganke Granules in terms of appearance, size, color, weight, taste and smell to ensure the blindness of the entire clinical trial. Summary of the invention

[0010] In view of the above technical problems, the present invention provides a simulation agent of Xingqin Ganke granules and a preparation method thereof. The simulation agent prepared by the present invention is basically consistent with Xingqin Ganke granules in appearance, color, smell and taste, and is not easily distinguished by researchers and clinical trial subjects, which can effectively prevent bias or breaking of blinds in clinical trials and ensure the smooth implementation of clinical trials.

[0011] In order to achieve the above technical effects, the present invention adopts the following technical solutions:

[0012] A composition for preparing a Chinese medicine granule simulant, comprising the following components:

[0013] Filler 96.30-99.12%, colorant 0.08-0.7%, flavoring agent 0.3-1.0%, suspending agent 0.5-2%, and the total mass percentage of each component is 100%;

[0014] Wherein, the filler is selected from dextrin and / or soluble starch; the colorant is selected from one or more of indigo pigment, brilliant blue pigment, sunset yellow pigment, lemon yellow pigment and carmine; the flavoring agent includes bittering agent, sweetener, acidulant and flavor; the suspending agent is sodium carboxymethyl cellulose;

[0015] The Chinese medicine granules are Xingqin Ganke granules prepared from scutellaria baicalensis, boiled bitter almonds, platycodon grandiflorum, liquorice, peucedanum peucedanum and bupleurum.

[0016] Preferably, the filler is dextrin and soluble starch; based on the total mass of the filler, dextrin accounts for 50%-65%, and the remainder is soluble starch.

[0017] More preferably, the filler is dextrin and soluble starch; based on the total mass of the filler, dextrin accounts for 55%-65%, and the remainder is soluble starch.

[0018] Most preferably, the filler is dextrin and soluble starch, and based on the total mass of the filler, dextrin accounts for 65% and the remainder is soluble starch.

[0019] Preferably, the colorant is selected from the group consisting of indigo pigment, brilliant blue pigment, sunset yellow pigment, lemon yellow pigment and carmine; based on the total mass of the simulant, the mass percentage of each colorant is:

[0020] Indigo pigment 0.001-0.005%, brilliant blue pigment 0.001-0.01%, sunset yellow pigment 0.01-0.1%, lemon yellow pigment 0.05-0.5%, carmine 0.02-0.04%.

[0021] Preferably, the bittering agent is sucrose octaacetate; based on the total mass of the mimetic agent, the mass percentage of sucrose octaacetate is 0.05-0.3%.

[0022] Preferably, the sweetener is steviol glycoside; based on the total mass of the mimetic agent, the mass percentage of steviol glycoside is 0.2-0.4%.

[0023] Preferably, the acidulant is citric acid; based on the total mass of the simulant, the mass percentage of citric acid is 0.06-0.14%.

[0024] Preferably, the aroma is selected from caramel aroma powder essences and burnt malt aroma powder essences.

[0025] More preferably, based on the total mass of the simulant, the mass percentage of the caramel flavor powder essence is 0.01-0.07%.

[0026] More preferably, based on the total mass of the simulant, the mass percentage of the burnt malt flavor powder essence is 0.01-0.08%.

[0027] Also preferably, the mass percentage of the suspending agent is 0.5-1%, most preferably 0.8-1%.

[0028] As a preferred embodiment, the present invention provides a composition I for preparing a Xingqin Ganke granule simulation agent, which is composed of the following components by mass percentage:

[0029] Dextrin 50-80%, sucrose octaacetate 0.05-0.3%, stevioside 0.2-0.4%, citric acid 0.06-0.14%, caramel flavor powder flavor 0.01-0.07%, burnt wheat flavor powder flavor 0.01-0.08%, indigo pigment 0.001-0.005%, brilliant blue pigment 0.001-0.01%, sunset yellow pigment 0.005-0.02%, lemon yellow pigment 0.05-0.2%, carmine 0.01-0.05%, sodium carboxymethyl cellulose 0.8-1%, and the balance is soluble starch.

[0030] As a more preferred embodiment, the present invention provides a composition Ia for preparing a Xingqin Ganke granule simulation agent, which is composed of the following components by mass percentage:

[0031] Dextrin 60-64%, sucrose octaacetate 0.08-0.20%, stevioside 0.25-0.35%, citric acid 0.10-0.12%, caramel flavor powder flavor 0.01-0.04%, burnt wheat flavor powder flavor 0.03-0.06%, indigo pigment 0.002-0.003%, brilliant blue pigment 0.004-0.006%, sunset yellow pigment 0.008-0.012%, lemon yellow pigment 0.07-0.09%, carmine 0.02-0.04%, sodium carboxymethyl cellulose 0.8-1%, and the balance is soluble starch.

[0032] Preferably, in the above composition 1a, the mass ratio of the colorant is:

[0033] Indigo pigment: brilliant blue pigment: sunset yellow pigment: lemon yellow pigment: carmine = 1: (2-2.5): (4-4.5): (34.5-35.5): (1-1.5).

[0034] Preferably, in the above composition Ia, the mass ratio of sucrose octaacetate, steviol glycoside and citric acid is:

[0035] Sucrose octaacetate:stevioside:citric acid=1:(2.8-3.0):(1.1-1.2).

[0036] Preferably, the weight proportions of the scutellaria baicalensis, boiled bitter almonds, platycodon grandiflorum, liquorice, peucedanum chinense and bupleurum are:

[0037] 400 parts of Scutellariae, 300 parts of boiled bitter almonds, 300 parts of Platycodon grandiflorum, 200 parts of Licorice, 400 parts of Peucedanum, and 400 parts of Bupleurum.

[0038] Also preferably, the Xingqin Ganke granules are prepared by the following method:

[0039] Add water to the above six ingredients and boil them twice, each time for 1.5 hours. Filter the decoction and concentrate it to an extract with a relative density of 1.15-1.20 g / ml (65°C). Add appropriate amount of dextrin and flavor correctors, granulate, and make 1000 g of granules.

[0040] The Xingqin Ganke granules prepared according to the above method are light yellow to yellow-brown granules with a slight fragrance and a bitter taste. One bag of Xingqin Ganke granules (11 g) is added with 200 ml of warm water and stirred to obtain a light yellow to yellow-brown solution with a slight fragrance and a slightly bitter taste.

[0041] Another object of the present invention is to provide a simulation agent of Xingqin Ganke granules, using the composition of the present invention, the composition I or the composition Ia as a raw material.

[0042] In addition, the present invention also provides a method for preparing a simulation agent of the Xingqin Ganke granules, comprising the following steps:

[0043] I. Preparation

[0044] Weigh each component according to composition I or composition Ia;

[0045] II. Mix indigo pigment, brilliant blue pigment, sunset yellow pigment, lemon yellow pigment, carmine pigment, stevioside and citric acid, add water, stir and dissolve to obtain a mixed aqueous solution; add sucrose octaacetate to 95% ethanol, stir and dissolve to obtain an alcohol solution;

[0046] III. Sodium carboxymethyl cellulose, dextrin and soluble starch are placed in a high-speed stirring granulator, and the mixed aqueous solution and the alcohol solution obtained in step II are added and stirred to form wet granules;

[0047] IV. Dry the wet granules obtained in step III until the moisture content of the granules is ≤6%, make the granules whole, add flavor and mix evenly, and pack them according to the same packing quality as Xingqin Ganke granules;

[0048] V. Perform turbidity measurement, color difference ΔE measurement, sedimentation volume ratio measurement and manual evaluation on the simulator obtained in step IV in parallel with the Xingqin Ganke Granules. The qualified ones are used as placebos in a blind placebo-controlled clinical study of the Xingqin Ganke Granules.

[0049] Preferably, in step II, the mass of water is 0.26-0.27 times the total mass of the composition I or the composition Ia, and most preferably 0.265 times.

[0050] Preferably, in step II, the volume of 95% ethanol is 0.1-0.125 times the total mass of composition I or composition Ia; more preferably 0.1 times.

[0051] Preferably, in step III, sodium carboxymethyl cellulose, dextrin and soluble starch are placed in a high-speed stirring granulator and stirred for 1-2 minutes at a stirring speed of 500-800 rpm and a cutting speed of 800-1000 rpm; the mixed aqueous solution and the alcohol solution obtained in step II are added, and stirring is continued for 1-2 minutes while maintaining the speed.

[0052] Preferably, in step IV, the drying temperature of the wet granules is 60-80° C. and the drying time is 1-2 hours.

[0053] Also preferably, in step IV, the mesh size of the sieve used for granulation is 18 meshes.

[0054] Preferably, in step V, the turbidity measurement is performed as follows:

[0055] (1) Preparation of test solution and control solution

[0056] Take about 8g-14g of the simulant, put it in a beaker, dissolve it with hot water, and prepare a test solution containing about 0.1g of the simulant per 1ml; take Xingqin Ganke granules, and obtain a control solution in the same way;

[0057] (2) Determination

[0058] 200 μL of the test solution, control solution and blank solvent were added dropwise to a 96-well plate, and the OD value was detected at 600 nm; wherein the blank solvent was water;

[0059] (3) Result judgment

[0060] After deducting the blank solvent absorption, the difference in OD values ​​between the test solution and the control solution should be between ±0.2.

[0061] Preferably, in step (1), the sampling amount of the simulator or Xingqin Ganke granules is 10g-12g; most preferably, the sampling amount of the simulator or Xingqin Ganke granules is 11g, which is placed in a beaker and dissolved with 110ml of hot water.

[0062] Preferably, in step V, the color difference value ΔE is measured according to the following operation:

[0063] A. Preparation of Test and Reference Solutions

[0064] Take 8-14g of the simulant, put it in a beaker, add hot water to dissolve it, and prepare a test solution containing about 0.1g of the simulant per 1ml; take Xingqin Ganke granules and obtain a control solution in the same way;

[0065] B. Preparation of Colorimeter

[0066] Preheat the colorimeter for 30±5 minutes. After preheating, adjust the black first and then the white.

[0067] C. Determination

[0068] Each sample was measured three times in parallel, and L*, a*, and b* were recorded and averaged. ΔL*, Δa*, and Δb* of the test solution and the reference solution were calculated and substituted into formula (I) to calculate the ΔE* value:

[0069] ΔE=(ΔL* 2 +Δa* 2 +Δb* 2 ) 1 / 2 (I)

[0070] Wherein, ΔE: color difference value; ΔL*: brightness difference between the test solution and the reference solution; Δa*: red-green difference between the test solution and the reference solution; Δb*: yellow-blue difference between the test solution and the reference solution;

[0071] D. Result judgment

[0072] ΔE should be between 1.0-2.0.

[0073] In the above formula (1), ΔL* is the brightness difference between the test solution and the reference solution. If it is a positive value, it means that the test sample is brighter, and if it is a negative value, it means that the test sample is darker; Δa* is the red-green difference between the test solution and the reference solution. If it is a positive value, it means that the test sample is redder, and if it is a negative value, it means that the test sample is greener; Δb* is the yellow-blue difference between the test solution and the reference solution. If it is a positive value, it means that the test sample is yellower, and if it is a negative value, it means that the test sample is bluer.

[0074] Preferably, in step V, the sedimentation volume ratio is determined as follows:

[0075] Take 5 g of the simulant and place it in a 50 mL stoppered measuring cylinder. Add 70°C to 80°C hot water to the scale line and shake vigorously for 2 minutes. When the test sample is evenly distributed in the solution, add hot water to make the volume 50 mL. After shaking evenly, read the height H0 of the suspension at this time. Let it stand for 3 hours, read the height H of the final sediment, and calculate the 3 h sedimentation volume ratio according to H / H0; the sedimentation volume ratio should be ≥0.75.

[0076] Preferably, in step V, the manual evaluation includes the following operations:

[0077] 1. Recruit and screen volunteers according to the following criteria

[0078] ① Sensitive sense of taste and smell, especially sensitive to sweetness, bitterness and odor;

[0079] ② The subjects were aged between 20 and 50 years old;

[0080] ③No drinking or smoking in the last 2 days;

[0081] ④ Do not eat 2 hours before tasting the solution, especially do not eat irritating food or drink food that strongly stimulates the taste buds;

[0082] 2. Preparation of test solution

[0083] Take 1 bag of the simulant and 1 bag of Xingqin Ganke granules respectively, add 200 ml of 70-80°C hot water to each, stir to dissolve, and obtain the simulant test solution and the Xingqin Ganke granules test solution; prepare three portions of the simulant test solution and the Xingqin Ganke granules test solution in parallel;

[0084] 3. Manual evaluation

[0085] The volunteers screened in step 1 were blindly asked to taste all the simulant test solutions and the Xingqin Ganke granules test solutions, and then score the color, smell, bitterness, sweetness, sourness, saltiness and astringency of each test solution, and calculate the average score of each item; the scoring criteria are as follows:

[0086] 0 points - none, 1 point - weak, mild, 2 points - moderate, 3 points - strong, 4 points - extremely strong;

[0087] The average scores of the color and odor of the simulant test solution should be the same as the corresponding average scores of the Xingqin Ganke Granules test solution, and the differences in the other items should be between ±0.2.

[0088] In this article, unless otherwise specified, the "water" mentioned above is purified distilled water.

[0089] The present invention examines and optimizes fillers, suspending agents, flavoring agents, colorants, etc. item by item, and finally provides a simulator that is very similar to the Chinese medicine Class I new drug Xingqin Ganke granules in shape, smell, and taste, thereby ensuring the smooth implementation of the clinical double-blind trial of the new drug and making the clinical data more authentic and reliable. BRIEF DESCRIPTION OF THE DRAWINGS

[0090] The present invention will be further described below in conjunction with the accompanying drawings

[0091] Figure 1 The photo shows various brown pigment solutions of different concentrations, where:

[0092] Row A, columns 1-6 are caramel color P440 solutions with concentrations from low to high; Row B, columns 1-6 are caramel color P460 solutions with concentrations from low to high; Row C, columns 1-6 are cocoa brown solutions with concentrations from low to high; Row D, columns 1-6 are milk chocolate brown solutions with concentrations from low to high; the 7th column of each row is Xingqin Ganke granule solution.

[0093] Figure 2 The photo shows various yellow pigment solutions of different concentrations, where:

[0094] Row A, columns 1-6 are lemon yellow solutions with concentrations from low to high; Row B, columns 1-6 are sunset yellow solutions with concentrations from low to high; Row C, columns 1-6 are egg yolk solutions with concentrations from low to high; Row D, columns 1-6 are sunset yellow solutions with concentrations from low to high; the 7th column of each row is the Xingqin Ganke granule solution.

[0095] Figure 3 The photos show the Xingqin Ganke granules prepared in Example 1 and the simulants prepared in Examples 2-5; in the figure:

[0096] 1: Xingqin Ganke Granules of Example 1; 2: Simulation of Example 2; 3: Simulation of Example 3; 4: Simulation of Example 4; 5: Simulation of Example 5. DETAILED DESCRIPTION

[0097] The present invention is described below with reference to specific examples. It will be appreciated by those skilled in the art that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention in any way.

[0098] The experimental methods in the following examples are all conventional methods unless otherwise specified. The medicinal materials, reagents, etc. used in the following examples are all commercially available products unless otherwise specified. The purchase of some reagents and raw materials is as follows:

[0099] Dextrin: Jiaxing Bailang Starch Products Co., Ltd., batch number: 20220912;

[0100] Soluble starch: Hanzhong Qinfa Dextrin Co., Ltd., batch number 221103;

[0101] Sucrose octaacetate: Zhejiang Hetang Technology Co., Ltd., batch number AA220723;

[0102] Stevioside: Qufu Shengren Pharmaceutical Co., Ltd., batch number 20230204;

[0103] Citric acid: Hunan Jiudian Hongyang Pharmaceutical Co., Ltd., batch number TF81220601;

[0104] Indigo pigment: Shanghai Dyestuff Research Institute Co., Ltd., batch number 11119002;

[0105] Brilliant blue pigment: Shanghai Dyestuff Research Institute Co., Ltd., batch number 10819010;

[0106] Sunset yellow pigment: Shanghai Dyestuff Research Institute Co., Ltd., batch number 112219052;

[0107] Lemon yellow pigment: Shanghai Dyestuff Research Institute Co., Ltd., batch number 12118139;

[0108] Carmine: Shanghai Dyestuff Research Institute Co., Ltd., batch number 10110018;

[0109] Sodium carboxymethyl cellulose: produced by Anhui Shanhe Pharmaceutical Excipients Co., Ltd., batch number 180413;

[0110] Caramel flavor powder flavor: Sino-US joint venture Yilun (Shanghai) Flavors and Fragrances Co., Ltd., batch number CP211215;

[0111] Burnt wheat flavor powder flavor: Sino-US joint venture Yilun (Shanghai) Flavors and Fragrances Co., Ltd., batch number CP230905;

[0112] Turbidimeter: Synergy 2, Bio-teck, USA;

[0113] Colorimeter: Beijing Chentai Instrument Technology Co., Ltd.; Model: ADCI-60-C.

[0114] Example 1 Preparation of Xingqin Ganke Granules

[0115] Prescription (0.9091 g = 1 weight portion): 363.64 g of Scutellaria baicalensis, 272.73 g of boiled bitter almond, 272.73 g of Platycodon grandiflorum, 181.82 g of Licorice, 363.64 g of Peucedanum chinense, and 363.64 g of Bupleurum chinense;

[0116] Preparation method: Add water to the above six ingredients and boil them twice, each time for 1.5 hours. Filter the decoction and concentrate it to an extract with a relative density of 1.10-1.25g / ml (60°C). Add appropriate amount of dextrin and flavor correctors, granulate, and make 1000g of granules.

[0117] Specification: 11g per bag.

[0118] According to the above prescription and preparation method, several batches of Xingqin Ganke granules were prepared, which had the following characteristics:

[0119] Solid: This product is light yellow to yellow-brown granules; slightly fragrant and bitter.

[0120] Liquid: Add 1 bag of Xingqin Ganke Granules (11g) to 200ml of warm water and stir to obtain a light yellow to yellow-brown solution with a slight fragrance and a slightly bitter taste.

[0121] Research example Study on the prescription and preparation method of Xingqin Ganke granules

[0122] 1. Study on the Simulant Prescription

[0123] 1.1 Screening of fillers

[0124] Take the fillers shown in Table 1, 10g each, dissolve them in 100mL hot water at 80, 60 and 40℃, take 200μL and add them dropwise to a 96-well plate, and use a microplate reader to detect the OD value at 600nm. At the same time, the OD value of the Xingqin Ganke granules prepared in Example 1 was measured in parallel (test sample preparation method: take 11g (1 bag) of the Xingqin Ganke granules, place them in a beaker, add 110ml of hot water to dissolve them, and prepare a test sample solution containing about 0.1g of Xingqin Ganke granules per 1ml). The larger the OD value, the higher the turbidity of the solution, and the results are shown in Table 1.

[0125] Table 1 OD value measurement results of different fillers at different temperatures

[0126]

[0127] As shown in Table 1, inulin, powdered sugar and maltodextrin are clear solutions, which are not affected by temperature and have little contribution to turbidity simulation; pregelatinized starch and corn starch gelatinize at 80°C, and the solution viscosity cannot be measured. Therefore, dextrin and soluble starch were preliminarily screened for subsequent research.

[0128] Dextrin and soluble starch were weighed in the proportions shown in Table 2, respectively, and dissolved in 100 mL of hot water at 80, 60, and 40°C, respectively, and 200 μL was added dropwise to a 96-well plate, and the OD value was detected at 600 nm using an ELISA reader. The OD value of the Xingqin Ganke granules prepared in Example 1 was measured in parallel. The results are shown in Table 2.

[0129] Table 2 OD value determination results of different proportions of fillers at different temperatures

[0130]

[0131] Table 2 shows that, taking the Xingqin Ganke granule solution brewed with 80°C water as a benchmark, among the different filler combinations tested, the turbidity of the filler combination with a dextrin ratio of 50%-65% is closer to it, among which the turbidity of the filler combination with a dextrin ratio of 55%-65% is closer to it, and the filler combination with a dextrin ratio of 65% is the closest.

[0132] Based on the above results, it is determined that the fillers of the simulation agent are dextrin and soluble starch; based on the total mass of the filler, dextrin accounts for about 50%-65%, preferably about 55%-65%, most preferably about 65%, and the remainder is soluble starch.

[0133] 1.2 Screening of suspending agents:

[0134] The above-mentioned preferred fillers dextrin and soluble starch increase the turbidity of the placebo solution and reduce the light transmittance, but because of the solubility, dextrin and soluble starch in the solution will settle, resulting in obvious stratification, which interferes with the similarity between the placebo and the Xingqin Ganke granules. In order to delay the sedimentation of insoluble matter in the solution and improve the solution stratification phenomenon, it is necessary to add an appropriate amount of suspending agent. According to the sedimentation volume ratio determination method, the types and amounts of the suspending agents shown in Table 3 are investigated to screen suitable suspending agents and amounts. The results are shown in Table 3.

[0135] Sedimentation volume ratio determination method: Weigh the suspending agent according to the mass volume percentage concentration shown in Table 3, place it in a 50mL stoppered measuring cylinder, add 70℃~80℃ hot water to the scale line, shake vigorously for 2min, and when the test sample is evenly distributed in the solution, add hot water to make the volume 50mL. After shaking evenly, read the starting height H0 of the suspension. After standing, read the final height H of the suspension, and calculate the sedimentation volume ratio at different time points according to H / H0.

[0136] Table 3 Sedimentation volume ratio determination results of different suspending agents

[0137]

[0138] The results showed that the suspending effect of 0.5-1% CMC-Na was better than that of other suspending agents, and the suspending effect of 0.8-1% CMC-Na was the best. Therefore, the prescription of the simulant suspending agent was determined.

[0139] 1.3 Screening of colorants:

[0140] The solution of Xingqin Ganke Granules is light yellow to yellow-brown, turbid and opaque, with low clarity. Since the solution enters the mouth when taken by patients, the pigment simulation scheme in liquid state is explored first, and then further optimized to ensure the similarity between the simulator and Xingqin Ganke Granules in solid state.

[0141] The types and proportions of pigments were examined by combining manual evaluation with objective evaluation (colorimeter).

[0142] 1.3.1 Screening of brown pigments:

[0143] Based on the brown-yellow hue of Xingqin Ganke granules, a pigment with a brown hue was selected for color simulation. Brown pigments (caramel pigment, cocoa brown and milk chocolate brown pigment) were prepared with water into solutions with the concentrations shown in Table 4. Figure 1 shown.

[0144] Preheat the colorimeter for 30±5min. After preheating, adjust the color to black first and then to white. Then measure each solution in parallel 3 times. Record L*, a*, and b*. Use the same method to measure the L*, a*, and b* of the Xingqin Ganke Granule Solution (take about 11g (1 bag of the Xingqin Ganke Granule), put it in a beaker, add 110ml of hot water to dissolve it, and prepare a test solution containing about 0.1g of Xingqin Ganke Granules per 1ml.). Based on the measured values ​​of the Xingqin Ganke Granule Solution, calculate ΔL*, Δa*, and Δb*, and substitute them into formula (I) to calculate the ΔE* value:

[0145] ΔE=(ΔL* 2 +Δa* 2 +Δb* 2 ) 1 / 2 (I)

[0146] Where, ΔE: color difference value;

[0147] ΔL*: The brightness difference with the Xingqin Ganke granule solution. If it is a positive value, it means that the tested sample is brighter, and a negative value means that the tested sample is darker.

[0148] Δa*: The red-green difference between the solution of Xingqin Ganke granules. If it is a positive value, it means that the sample being tested is reddish, and if it is a negative value, it means that the sample being tested is greenish.

[0149] Δb*: The difference between the yellow and blue of the Xingqin Ganke granule solution. If it is a positive value, it means that the tested sample is yellowish, and a negative value means that the tested sample is blue.

[0150] The results are shown in Table 4.

[0151] Table 4 Lab values ​​and color difference values ​​of different concentrations of brown pigments

[0152]

[0153] Depend on Figure 1 It can be seen that the color tone of milk chocolate brown is orange-red, which is quite different from the brown-yellow color of Xingqin Ganke granules solution; although the color tones of caramel pigment and cocoa brown are similar to those of Xingqin Ganke granules, the overall color is still lighter, ΔE>6.0 (as shown in Table 4), which is quite different from Xingqin Ganke granules. Increasing the concentration of pigments will have safety risks, so a variety of brown pigments should be used.

[0154] 1.3.2 Screening of yellow pigments:

[0155] The solution and granules of Xingqin Ganke Granules are both brownish yellow, so it is necessary to use brown pigments in combination with yellow pigments. Yellow pigments (lemon yellow, sunset yellow, egg yolk and sunset pigments) are prepared according to the concentrations in Table 5 and L*, a* and b* are recorded using a colorimeter. Figure 2 The same method was used to determine the L*, a*, and b* of the Xingqin Ganke Granule Solution (preparation method is the same as in Section 1.3.1). Based on the measured values ​​of the Xingqin Ganke Granule Solution, ΔL*, Δa*, and Δb* were calculated and substituted into formula (I) to calculate the ΔE* value. The results are shown in Table 5.

[0156] Table 5 Lab values ​​and color difference values ​​of different concentrations of yellow pigments

[0157]

[0158] From the results in Table 5, it can be seen that the yellow pigment solutions are very different from the Xingqin Ganke granules and should only be used in small amounts to blend brown pigments. Figure 2 It shows that lemon yellow and egg yolk are yellowish, while sunset yellow and sunset color are orange.

[0159] 1.3.3 Screening of mixed pigments:

[0160] The L value represents the lightness of the color, and is used to screen brown pigments in this experiment. The colorimeter was used to screen out brown pigments with L values ​​of about 17 to 19 in the brown color system - 0.4% caramel color P440, 0.4% caramel color P460, 0.05% cocoa brown, and 0.05% milk chocolate brown in mass percentage concentration. The +b value represents yellow, and is used to screen yellow pigments in this experiment. The colorimeter was used to screen out yellow pigments with +b values ​​of about 12 to 15 in the yellow color system - 0.01% lemon yellow, 0.015% sunset yellow, 0.015% egg yolk, and 0.025% sunset color in mass percentage concentration.

[0161] After manual evaluation (visual observation), the milk chocolate brown solution was excluded first because it was reddish and had a large color difference with the Xingqin Ganke granules. The ΔE of 0.4% caramel color P460 in caramel color was less than the ΔE of 0.4% caramel color P440, which was closer to the Xingqin Ganke granules, so P460 caramel color was selected. The mixed color solution was prepared as shown in Table 6, and then manually evaluated (visual observation), and the results are shown in Table 6.

[0162] Table 6 Mixed pigment screening results

[0163]

[0164] Based on the above investigation, the color simulation prescription scheme 1 of the simulator is 0.55% caramel color P460+0.05% cocoa brown+0.04% lemon yellow.

[0165] 1.3.4 Simulation using three primary colors (red, yellow, and blue)

[0166] The three optical colors are red, green and blue, but in the field of art, the three primary colors are red, yellow and blue, which can be mixed to produce all colors, and are more suitable for the color simulation of Chinese medicine placebos. Carmine, lemon yellow and brilliant blue are mainly used as the three-color combination for simulation, and sunset yellow and indigo are used to optimize the prescription.

[0167] The mixed pigment solution was prepared as shown in Table 7, and then manually evaluated (observed with the naked eye). The results are shown in Table 7.

[0168] Based on the above investigation results, the pigment simulation prescription scheme 2 of the simulator is 0.032% carmine + 0.084% lemon yellow + 0.01% sunset yellow + 0.005% brilliant blue + 0.0024% indigo.

[0169] Table 7 Three primary color pigment screening results

[0170]

[0171] 1.3.5 Determination of pigment simulation prescription

[0172] The pigment simulation formula scheme 2 is based on the pigment simulation formula scheme 1 and optimizes the brown-yellow color. According to manual evaluation, the color of the formula 2 is closer to that of the Xingqin Ganke granules. Therefore, the simulation agent colorant formula of the present invention is preferably the formula 2.

[0173] 1.4 Screening of flavor correctives (taste simulation prescriptions)

[0174] 1.4.1 Screening of bittering agents:

[0175] Commonly used bittering agents include naringin, neohesperidin, and matrine. However, the above substances are all medicinal active ingredients and may produce physiological activity, which may have an adverse effect on the clinical double-blind trial of Xingqin Ganke Granules; therefore, sucrose octaacetate was selected as a bittering agent. Blank granules were prepared with the optimal fillers and colorants. 11g of blank granules were taken, 110ml of hot water was added to dissolve, and a solution with a concentration of about 0.1g / ml was prepared; based on the amount of filler, different proportions of sucrose octaacetate were added to the blank granule solution as shown in Table 8, and artificial evaluation was performed. The results are shown in Table 8.

[0176] Table 8 Bitterness concentration screening results

[0177]

[0178] Table 8 shows that when the concentration of sucrose octaacetate is 0.1%, the bitterness is close to that of Xingqin Ganke Granules.

[0179] 1.4.2 Screening of sweeteners

[0180] Stevioside is added as a flavoring agent in the prescription of Xingqin Ganke Granules. In order to simulate the sweet taste of Xingqin Ganke Granules to the greatest extent, the simulator also prefers stevioside for sweetness simulation. Prepare blank granules with the selected fillers and colorants. Take 11g of blank granules, add 110ml of hot water to dissolve, and prepare a solution with a concentration of about 0.1g / ml; based on the amount of filler, add different proportions of stevioside to the blank granule solution as shown in Table 9, and conduct manual evaluation. The results are shown in Table 9.

[0181] Table 9 Sweetener screening results

[0182]

[0183] Table 9 shows that when the stevioside concentration is 0.3%, the sweetness is close to that of Xingqin Ganke Granules.

[0184] 1.4.3 Screening of acidulants:

[0185] Blank particles were prepared with the optimal fillers and colorants. 11 g of blank particles were taken and dissolved in 110 ml of hot water to prepare a solution with a concentration of about 0.1 g / ml; based on the amount of filler, different proportions of citric acid were added to the blank particle solution as shown in Table 10, and manual evaluation was performed. The results are shown in Table 10.

[0186] Table 10 Acidulant screening results

[0187]

[0188] Table 10 shows that when the citric acid concentration is 0.12%, the sour taste is close to that of Xingqin Ganke Granules.

[0189] Based on the above considerations, the taste simulation formula of the simulation agent is preferably 0.1% sucrose octaacetate+0.3% steviol glycoside+0.12% citric acid based on the total mass of the filler.

[0190] 2. Research on preparation methods

[0191] Fluidized bed boiling granulation and high shear wet granulation were used as the main granulation methods to explore a more suitable granulation method.

[0192] 2.1 Fluidized bed granulation

[0193] Base material: dextrin and soluble starch (65:35), total 200g;

[0194] Top spray liquid: 20% pvp aqueous solution, colorant aqueous solution (tartrazine, sunset yellow, carmine, brilliant blue and indigo (mass ratio 64:20:32:5) 0.262 g in total, dissolved in 50 ml water), flavoring solution (sucrose octaacetate, steviol glycoside and citric acid (mass ratio 10:30:12:3) 1.04 g in total, dissolved in 25 ml 95% ethanol);

[0195] Key parameters: Control the air inlet temperature below 80℃ and the air inlet frequency below 20Hz. Start spraying the pvp solution when the temperature is about 60℃, and control the atomization pressure below 0.4Mpa. Colorant aqueous solution at the same temperature and air inlet frequency. Adjust the air inlet temperature below 40℃, spray the flavoring solution, and control the atomization pressure below 1.0Mpa. After drying, pass through No. 1 and No. 5 sieves, add 0.06g caramel flavor powder essence, 0.12g burnt wheat flavor powder essence, and 2g sodium carboxymethyl cellulose for total mixing, mixing time 30min, speed 20r / min, and finally collect qualified particles.

[0196] Visual inspection revealed that the color of the fluidized bed boiling granules was too light, and was quite different from the color of the Xingqin Ganke granules.

[0197] 2.2 High Shear Wet Granulation

[0198] Base material: dextrin and soluble starch (65:35), total 200g;

[0199] Mixed solution: colorant aqueous solution (a total of 0.262 g of lemon yellow, sunset yellow, carmine, brilliant blue and indigo (mass ratio 64:20:32:5), dissolved in 50 ml of water), flavoring solution (a total of 1.04 g of sucrose octaacetate, steviol glycoside and citric acid (mass ratio 10:30:12:3), dissolved in 25 ml of 95% ethanol);

[0200] Key parameters: Mixing speed is 800rpm, chopping speed is 1000rpm, about 2min. Granulation stirring speed is 800rpm, chopping speed is 1000rpm, about 2min. The order of solutions in the granulation process is colorant aqueous solution first, then flavoring solution. After drying, granulate, pass through No. 1 and No. 5 sieves, add 0.06g caramel flavor powder essence, 0.12g burnt wheat flavor powder essence, and 2g sodium carboxymethyl cellulose for total mixing, mixing time 30min, speed 20r / min, and finally collect qualified particles.

[0201] Visual observation revealed that the color of the simulant obtained by high shear wet granulation was similar to that of the Xingqin Ganke granules. Therefore, high shear wet granulation was preferred for preparing the simulant of the present invention.

[0202] The study also found that the amount of water added during high shear wet granulation determines the color of the final granules: if the amount added is not enough, the granules are lighter in color; if the amount added is too much, the granules are too dark in color and tend to clump together. While ethanol is used as a solvent for sucrose octaacetate, it has a certain wetting and dispersing effect. If it is added in too much, the viscosity of the soft material will increase, resulting in clumping. The amount of alcohol and water added needs to be investigated. With 200g of the base material, granules were prepared according to the amount of water and 95% ethanol shown in Table 11, and then the color and appearance of the granules were evaluated. The results are shown in Table 11.

[0203] Table 11 Investigation results of water and alcohol addition during high shear wet granulation (200 g)

[0204]

[0205] The results in Table 11 show that the corresponding amount of water added for the laboratory test scale (200 g) is 53 mL, and the amount of alcohol added is 20 mL. That is, optimally, the amount of water used is about 0.265 times the total mass of the simulant composition, and the amount of 95% ethanol used is about 0.1 times the total mass of the simulant composition.

[0206] 2.3 Optimization of high shear granulation process

[0207] Simulation agent prescription: see Table 12.

[0208] Table 12 Simulant prescription

[0209]

[0210] Weigh each component according to the above prescription, and then granulate them according to the following process:

[0211] Process 1: Place indigo pigment, brilliant blue pigment, sunset yellow pigment, lemon yellow pigment, carmine pigment, stevioside and citric acid in a beaker, add 50ml purified water, stir to dissolve evenly to obtain a mixed aqueous solution. Add sucrose octaacetate to 25ml 95% ethanol, stir to dissolve, and obtain an alcohol solution. Place dextrin, soluble starch and sodium carboxymethyl cellulose in a high-speed stirring granulator, mix and stir for 2min, the stirring speed is 800rpm, and the cutting speed is 1000rpm. Slowly add the mixed aqueous solution and alcohol solution, after all are added, stir at the same speed for 1min, and find that the color is lighter; cover the lid and let it moisten for 10min, stir for 1min, and the color of the particles does not change; add 5mL water and stir for 1min, the color of the particles is similar to that of the Xingqin Ganke granules. Collect the particles and dry them at 60-80℃ for 1-2 hours; after drying, pass through an 18-mesh sieve for granulation, collect qualified particles, and calculate the yield to be 65.7%.

[0212] Process 2: Place indigo pigment, brilliant blue pigment, sunset yellow pigment, lemon yellow pigment, carmine pigment, stevioside and citric acid in a beaker, add 50 ml of purified water, stir to dissolve evenly to obtain a mixed aqueous solution. Add sucrose octaacetate to 20 ml of 95% ethanol, stir to dissolve, and obtain an alcohol solution. Place dextrin, soluble starch and sodium carboxymethyl cellulose in a high-speed stirring granulator, mix and stir for 2 minutes, the stirring speed is 800 rpm, and the chopping speed is 1000 rpm. Add 20mL of mixed aqueous solution and 20mL of alcohol solution, stir at the same speed for 1min, and it is found that there is basically no color; continue to add 15mL of mixed aqueous solution, stir at the same speed for 1min, the soft material turns slightly yellow, but still not colored; continue to add 15mL of mixed aqueous solution, stir at the same speed for 1min, the particles are basically colored, but relatively light; reduce the speed, the stirring speed is 500rpm, the cutting speed is 800rpm, continue to stir for 1.5min, and it is found that the particles are basically unchanged; add 1.5mL of alcohol solution (95% ethanol solution of sucrose octaacetate with a concentration of 0.01g / ml), continue to stir at the same speed for 1.5min, and it is found that the color is basically unchanged, and agglomerated particles appear; add 3mL of water, continue to stir at the same speed for 1.5min, and the color of the particles is similar to that of Xingqin Ganke granules. Collect the particles and dry them at 60-80℃ for 1-2 hours; after drying, pass through an 18-mesh sieve for granulation, collect qualified particles, and calculate the yield to be 68.8%.

[0213] Process 3: Place indigo pigment, brilliant blue pigment, sunset yellow pigment, lemon yellow pigment, carmine pigment, stevioside and citric acid in a beaker, add 53 ml of purified water, stir to dissolve evenly to obtain a mixed aqueous solution. Add sucrose octaacetate to 20 ml of 95% ethanol, stir to dissolve, and obtain an alcohol solution. Place dextrin, soluble starch and sodium carboxymethyl cellulose in a high-speed stirring granulator, mix and stir for 2 minutes, the stirring speed is 800 rpm, and the cutting speed is 1000 rpm. Slowly add the mixed aqueous solution and alcohol solution, after all are added, stir at the same speed for 1 minute, the color of the particles is similar to that of the Xingqin Ganke granules; reduce the speed, the stirring speed is 500 rpm, the chopping speed is 800 rpm, continue stirring for 1 minute, the particles become larger and the color becomes slightly darker. Collect the particles and dry them at 60-80℃ for 1-2 hours; after drying, pass through an 18-mesh sieve for whole particles, collect qualified particles, and calculate the yield to be 63.0%.

[0214] Process 4: Indigo pigment, brilliant blue pigment, sunset yellow pigment, lemon yellow pigment, carmine pigment, stevioside and citric acid are placed in a beaker, 53 ml of purified water is added, and the mixture is stirred to dissolve evenly to obtain a mixed aqueous solution. Sucrose octaacetate is added to 20 ml of 95% ethanol, and the mixture is stirred to dissolve to obtain an alcohol solution. Dextrin, soluble starch and sodium carboxymethyl cellulose are placed in a high-speed stirring granulator, and mixed and stirred for 2 min at a stirring speed of 800 rpm and a cutting speed of 1000 rpm. The mixed aqueous solution and alcohol solution are slowly added, and after all are added, they are stirred at the same speed for 2 min. The color of the particles is similar to that of the Xingqin Ganke granules. Continue stirring at the same speed for 1 min, the particles will clump together, the color will deepen, and the temperature in the pot will rise; continue stirring for another 1 min, the particles will clump together in large pieces, the color will continue to deepen, and the color will be too dark relative to the test preparation. Collect the particles and dry them at 60-80 ° C for 1-2 hours; after drying, pass through an 18-mesh sieve for granulation, collect qualified particles, and the calculated yield is 96.9%.

[0215] Based on the results of the above process investigation, the preferred granulation process parameters are:

[0216] 1) When preparing the mixed aqueous solution, the mass of water is 0.26-0.27 times, preferably 0.265 times, of the total mass of the simulant. When preparing the alcohol solution, the volume of 95% ethanol is 0.1-0.125 times, preferably 0.1 times, of the total mass of the simulant.

[0217] 2) During high shear wet granulation, dextrin, soluble starch and sodium carboxymethyl cellulose are placed in a high-speed stirring granulator, stirred at a stirring speed of 500-800 rpm and a cutting speed of 800-1000 rpm for 1-2 minutes, preferably at a stirring speed of 800 rpm and a cutting speed of 1000 rpm for 2 minutes; the mixed aqueous solution and the alcohol solution are added, and stirring is continued for 1-2 minutes while maintaining the speed.

[0218] 3) Dry the wet granules at 60-80°C for 1-2 hours.

[0219] Example 2 A kind of simulant of Xingqin Ganke granules

[0220] The simulation agent of this embodiment is made of the following composition as raw material (the total mass percentage of each component is 100%. 1 part = 1g):

[0221] 12800 parts of dextrin, 6851.32 parts of soluble starch, 6.4 parts of carmine pigment, 1 part of brilliant blue pigment, 0.48 parts of indigo pigment, 2 parts of sunset yellow pigment, 16.8 parts of lemon yellow pigment, 20 parts of sucrose octaacetate, 24 parts of citric acid, 60 parts of steviol glycosides, 6 parts of caramel flavor powder flavor, 12 parts of burnt wheat flavor powder flavor, and 200 parts of sodium carboxymethyl cellulose.

[0222] The simulant of this embodiment is prepared by the following process steps:

[0223] I. Preparation

[0224] Weigh each component according to the mass percentage of the composition;

[0225] II. After mixing indigo pigment, brilliant blue pigment, sunset yellow pigment, lemon yellow pigment, carmine pigment, stevioside and citric acid, add 5300 g of water and stir to dissolve to obtain a mixed aqueous solution; add sucrose octaacetate to 2000 ml of 95% ethanol and stir to dissolve to obtain an alcohol solution;

[0226] III. Sodium carboxymethyl cellulose, dextrin and soluble starch are mixed and placed in a high-speed stirring granulator, stirred at a stirring speed of 800 rpm and a cutting speed of 1000 rpm for 2 minutes; the mixed aqueous solution and the alcohol solution are added, and stirring is continued for 2 minutes at a maintained speed to form wet granules;

[0227] IV. The wet granules obtained in step III are dried at 80°C for 2 hours, and the moisture content is 5.7%. The granules are sieved through an 18-mesh sieve, flavorings are added and mixed evenly, and the granules are packaged according to the same packaging quality as the Xingqin Ganke granules.

[0228] Example 3 A kind of simulant of Xingqin Ganke granules

[0229] The simulation agent of this embodiment is made of the following composition as raw material (the total mass percentage of each component is 100%. 1 part = 1g):

[0230] 13870.262 parts of dextrin, 5944.398 parts of soluble starch, 4 parts of carmine pigment, 0.8 parts of brilliant blue pigment, 0.54 parts of indigo pigment, 2 parts of sunset yellow pigment, 12 parts of lemon yellow pigment, 10 parts of sucrose octaacetate, 12 parts of citric acid, 40 parts of steviol glycosides, 2 parts of caramel flavor powder essence, 2 parts of burnt wheat flavor powder essence, and 100 parts of sodium carboxymethyl cellulose.

[0231] The simulant of this example was prepared according to the same steps and substantially the same process as in Example 2, except that the drying temperature of the wet granules in step IV was 70°C.

[0232] Example 4 A kind of simulant of Xingqin Ganke granules

[0233] The simulation agent of this embodiment uses the composition consisting of the following components as raw materials (the total mass percentage of each component is 100%, 1 part = 1g):

[0234] 14795.1 parts of dextrin, 4931.7 parts of soluble starch, 6 parts of carmine pigment, 0.6 parts of brilliant blue pigment, 0.6 parts of indigo pigment, 2 parts of sunset yellow pigment, 14 parts of lemon yellow pigment, 16 parts of sucrose octaacetate, 16 parts of citric acid, 50 parts of steviol glycosides, 4 parts of caramel flavor powder flavor, 4 parts of burnt wheat flavor powder flavor, and 160 parts of sodium carboxymethyl cellulose.

[0235] The simulant of this example was prepared according to the same steps and substantially the same process as in Example 2, except that the drying temperature of the wet granules in step IV was 60°C.

[0236] Example 5 A kind of simulant of Xingqin Ganke granules

[0237] The simulation agent of this embodiment uses the composition consisting of the following components as raw materials (the total mass percentage of each component is 100%, 1 part = 1g):

[0238] 10795.18 parts of dextrin, 8832.42 parts of soluble starch, 7 parts of carmine pigment, 1 part of brilliant blue pigment, 0.4 parts of indigo pigment, 2 parts of sunset yellow pigment, 16 parts of lemon yellow pigment, 40 parts of sucrose octaacetate, 20 parts of citric acid, 70 parts of steviol glycosides, 8 parts of caramel flavor powder essence, 8 parts of burnt wheat flavor powder essence, and 200 parts of sodium carboxymethyl cellulose.

[0239] The simulation agent of this example was prepared according to the same steps and process as Example 2. Test CaseInvestigation of the Similarity between the Simulation Agents of Examples 2-5 and Xingqin Ganke Granules

[0240] 1. Turbidity measurement

[0241] Take 11 g of the Xingqin Ganke granules prepared in Example 1 and the simulants prepared in Examples 2-5, add 110 ml of water, stir, and make a solution of about 0.1 g / ml to obtain a test solution.

[0242] 200 μL of the test solution and blank solvent (purified water) were added dropwise to a 96-well plate, and the OD value was detected at 600 nm. The results are shown in Table 14.

[0243] Table 14 Summary of turbidity measurement results

[0244]

[0245] The results showed that the difference between the absorbance values ​​of the simulation agents of Example 2 and Example 5 and the absorbance value of the Xingqin Ganke granules was less than 0.2, and the turbidity measurement results were "consistent, qualified". The turbidity measurement results of the simulation agents prepared in other examples were "inconsistent, unqualified".

[0246] 2. Color difference measurement

[0247] Preparation of the test solution: Take 11 g of the Xingqin Ganke granules prepared in Example 1 and the simulants prepared in Examples 2-5, accurately weigh them, put them in 110 ml volumetric flasks respectively, add water to dissolve, and prepare a solution of about 0.1 g / ml to obtain the test solution.

[0248] Determination: Preheat the colorimeter for 30 minutes. After preheating, adjust the color to black first, then adjust the color to white. After completion, the measurement can be performed. Each sample is measured 3 times in parallel. Record L*, a*, and b*; based on the measured value of the Xingqin Ganke granule solution, calculate the ΔL*, Δa*, and Δb* of the simulant solution, and substitute them into formula (I) to calculate the ΔE* value:

[0249] ΔE=(ΔL* 2 +Δa* 2 +Δb* 2 ) 1 / 2 (I)

[0250] Results: See Table 15.

[0251] Table 15 Color difference value measurement results

[0252]

[0253] The color difference values ​​of the simulants of Example 2 and Example 5 are between 1.0 and 2.0, and the test results are "qualified", while the test results of other simulants are "unqualified".

[0254] 3. Sedimentation volume ratio determination:

[0255] Take 5g of each of the Xingqin Ganke granules prepared in Example 1 and the simulants prepared in Examples 2-5, place them in 50mL stoppered measuring cylinders, add hot water (70℃-80℃) to the scale line, shake vigorously for 2min, and when the test sample is evenly distributed in the solution, add hot water to 50mL, shake evenly, read the height H0 of the suspension at this time, read the height H of the final sediment after standing for 3 hours, and calculate the sedimentation volume ratio according to sedimentation ratio = H / H0. A sedimentation volume ratio of more than 0.75 is considered qualified.

[0256] The measurement results are shown in Table 16.

[0257] Table 16 Sedimentation volume ratio measurement results

[0258]

[0259] Table 16 shows that the sedimentation volume ratio of the simulants prepared in Example 2 and Example 5 is greater than 0.75, and this test item is "qualified", while the other simulants are "unqualified" in this test item.

[0260] 4. Human Evaluation

[0261] Volunteers were recruited and screened according to the following criteria:

[0262] ① Sensitive sense of taste and smell, especially sensitivity to sweetness, bitterness and odor; ② The age of the subjects should be controlled between 20 and 50 years old; ③ No drinking or smoking in the last 2 days; ④ No eating 2 hours before tasting the solution, especially no eating irritating food or drinking carbonated drinks and other foods that strongly stimulate the taste buds.

[0263] Preparation of the test solution: Take 1 bag of each of the simulation agents of Examples 2-5 and the Xingqin Ganke granules prepared in Example 1, add 200 ml of hot water (70-80° C.), stir to dissolve, and obtain the test solution.

[0264] Three qualified volunteers were blindly asked to rate the color, smell and taste of each test solution. The scoring criteria were: 0 points - none, 1 point - weak, slight, 2 points - moderate, 3 points - strong, 4 points - extremely strong.

[0265] The manual evaluation results were statistically analyzed after unblinding and are shown in Table 17.

[0266] Table 17 Manual evaluation results

[0267]

[0268]

[0269] The simulation agents of Example 2 and Example 5 are most similar to the Xingqin Ganke Granules in color, bitterness, sweetness, sourness, saltiness, astringency and smell.

[0270] In summary, the present invention provides a simulated agent of a traditional Chinese medicine preparation, Xingqin Ganke granules. Whether in solid or liquid form, the simulated agent is very similar to Xingqin Ganke granules in terms of color, smell, taste, etc., and can be used as a placebo in a clinical double-blind trial of the traditional Chinese medicine granules, thereby ensuring the accuracy of the clinical trial results.

Claims

1. A composition for preparing a Chinese medicine granule simulant, comprising the following components: Filler 96.30-99.12%, colorant 0.08-0.7%, flavoring agent 0.3-1.0%, suspending agent 0.5-2%, and the total mass percentage of each component is 100%; Wherein, the filler is selected from dextrin and / or soluble starch; the colorant is selected from one or more of indigo pigment, brilliant blue pigment, sunset yellow pigment, lemon yellow pigment and carmine; the flavoring agent includes bittering agent, sweetener, acidulant and flavor; the suspending agent is sodium carboxymethyl cellulose; The Chinese medicine granules are Xingqin Ganke granules prepared from scutellaria baicalensis, boiled bitter almonds, platycodon grandiflorum, liquorice, peucedanum peucedanum and bupleurum.

2. The composition according to claim 1, characterized in that The filler is dextrin and soluble starch; based on the total mass of the filler, dextrin accounts for 50%-65%, and the remainder is soluble starch; Preferably, the filler is dextrin and soluble starch; based on the total mass of the filler, dextrin accounts for 55%-65%, and the remainder is soluble starch; Most preferably, the filler is dextrin and soluble starch, and based on the total mass of the filler, dextrin accounts for 65% and the remainder is soluble starch; Also preferably, the mass percentage of the suspending agent is 0.5-1%, most preferably 0.8-1%.

3. The composition according to claim 1, characterized in that The colorant is selected from indigo pigment, brilliant blue pigment, sunset yellow pigment, lemon yellow pigment and carmine; based on the total mass of the simulant, the mass percentage of each colorant is: Indigo pigment 0.001-0.005%, brilliant blue pigment 0.001-0.01%, sunset yellow pigment 0.01-0.1%, lemon yellow pigment 0.05-0.5%, carmine 0.02-0.04%; Preferably, the bittering agent is sucrose octaacetate; based on the total mass of the simulating agent, the mass percentage of sucrose octaacetate is 0.05-0.3%; Preferably, the sweetener is steviol glycoside; based on the total mass of the mimetic agent, the mass percentage of steviol glycoside is 0.2-0.4%; Preferably, the acidulant is citric acid; based on the total mass of the simulant, the mass percentage of citric acid is 0.06-0.14%; Preferably, the fragrance is selected from all of caramel flavor powder essences and burnt wheat flavor powder essences; More preferably, based on the total mass of the simulant, the mass percentage of the caramel flavor powder essence is 0.01-0.07%; More preferably, based on the total mass of the simulant, the mass percentage of the burnt malt flavor powder essence is 0.01-0.08%.

4. The composition according to claim 1, characterized in that The composition is composition I, which consists of the following components by mass percentage: Dextrin 50-80%, sucrose octaacetate 0.05-0.3%, stevioside 0.2-0.4%, citric acid 0.06-0.14%, caramel flavor powder flavor 0.01-0.07%, burnt wheat flavor powder flavor 0.01-0.08%, indigo pigment 0.001-0.005%, brilliant blue pigment 0.001-0.01%, sunset yellow pigment 0.005-0.02%, lemon yellow pigment 0.05-0.2%, carmine 0.01-0.05%, sodium carboxymethyl cellulose 0.8-1%, and the balance is soluble starch.

5. The composition according to claim 1, characterized in that The composition is composition Ia, which is composed of the following components by mass percentage: Dextrin 60-64%, sucrose octaacetate 0.08-0.20%, stevioside 0.25-0.35%, citric acid 0.10-0.12%, caramel flavor powder essence 0.01-0.04%, burnt wheat flavor powder essence 0.03-0.06%, indigo pigment 0.002-0.003%, brilliant blue pigment 0.004-0.006%, sunset yellow pigment 0.008-0.012%, lemon yellow pigment 0.07-0.09%, carmine 0.02-0.04%, sodium carboxymethyl cellulose 0.8-1%, and the balance is soluble starch; Preferably, in the above composition 1a, the mass ratio of the colorant is: Indigo pigment: brilliant blue pigment: sunset yellow pigment: lemon yellow pigment: carmine = 1: (2-2.5): (4-4.5): (34.5-35.5): (1-1.5); Preferably, in the above composition Ia, the mass ratio of sucrose octaacetate, steviol glycoside and citric acid is: Sucrose octaacetate:stevioside:citric acid=1:(2.8-3.0):(1.1-1.2).

6. The composition according to claim 1, 4 or 5, characterized in that The weight proportions of the scutellaria baicalensis, boiled bitter almond, platycodon grandiflorum, liquorice, peucedanum chinense and bupleurum are as follows: 400 parts of Scutellariae Radix, 300 parts of boiled bitter almonds, 300 parts of Platycodon grandiflorum, 200 parts of Licorice, 400 parts of Peucedanum chinense, 400 parts of Bupleurum chinense; Also preferably, the Xingqin Ganke granules are prepared by the following method: Add water to the above six ingredients and boil them twice, each time for 1.5 hours. Filter the decoction and concentrate it to an extract with a relative density of 1.15-1.20 g / ml (65°C). Add appropriate amount of dextrin and flavor correctors, granulate, and make 1000 g of granules.

7. A simulation agent of Xingqin Ganke granules, using the composition according to any one of claims 1 to 3 as a raw material; Preferably, the simulation agent of the Xingqin Ganke granules is made from the composition I described in claim 4 or the composition Ia described in claim 5.

8. The method for preparing the simulation agent of Xingqin Ganke granules according to claim 7 comprises the following steps: I. Preparation Weigh each component according to composition I or composition Ia; II. Mix indigo pigment, brilliant blue pigment, sunset yellow pigment, lemon yellow pigment, carmine pigment, stevioside and citric acid, add water, stir and dissolve to obtain a mixed aqueous solution; add sucrose octaacetate to 95% ethanol, stir and dissolve to obtain an alcohol solution; III. Sodium carboxymethyl cellulose, dextrin and soluble starch are placed in a high-speed stirring granulator, and the mixed aqueous solution and the alcohol solution obtained in step II are added and stirred to form wet granules; IV. Dry the wet granules obtained in step III until the moisture content of the granules is ≤6%, make the granules whole, add flavor and mix evenly, and pack them according to the same packing quality as Xingqin Ganke granules; V. Perform turbidity measurement, color difference ΔE measurement, sedimentation volume ratio measurement and manual evaluation on the simulator obtained in step IV in parallel with the Xingqin Ganke Granules. The qualified ones are used as placebos in a blind placebo-controlled clinical study of the Xingqin Ganke Granules.

9. The preparation method according to claim 8, characterized in that: In step II, the mass of water is 0.26-0.27 times the total mass of the composition I or the composition Ia, and most preferably 0.265 times; Preferably, in step II, the volume of 95% ethanol is 0.1-0.125 times the total mass of the composition I or the composition Ia; more preferably 0.1 times; Preferably, in step III, sodium carboxymethyl cellulose, dextrin and soluble starch are placed in a high-speed stirring granulator, stirred for 1-2 minutes at a stirring speed of 500-800 rpm and a cutting speed of 800-1000 rpm; the mixed aqueous solution and the alcohol solution obtained in step II are added, and stirring is continued for 1-2 minutes at the maintained speed; Preferably, in step IV, the drying temperature of the wet granules is 60-80° C. and the drying time is 1-2 hours; Also preferably, in step IV, the mesh size of the sieve used for granulation is 18 meshes.

10. The preparation method according to claim 8, characterized in that: In step V, the turbidity measurement is performed as follows: (1) Preparation of test solution and control solution Take about 8g-14g of the simulant, put it in a beaker, dissolve it with hot water, and prepare a test solution containing about 0.1g of the simulant per 1ml; take Xingqin Ganke granules, and obtain a control solution in the same way; (2) Determination 200 μL of the test solution, control solution and blank solvent were added dropwise to a 96-well plate, and the OD value was detected at 600 nm; wherein the blank solvent was water; (3) Result judgment After deducting the absorption of the blank solvent, the difference in OD values ​​between the test solution and the control solution should be within ±0.2; Preferably, in step (1), the sample amount of the simulant or Xingqin Ganke granules is 10g-12g; most preferably, the sample amount of the simulant or Xingqin Ganke granules is 11g, which is placed in a beaker and dissolved in 110ml of hot water; Preferably, in step V, the color difference value ΔE is measured according to the following operation: A. Preparation of Test and Reference Solutions Take 8-14g of the simulant, put it in a beaker, add hot water to dissolve it, and prepare a test solution containing about 0.1g of the simulant per 1ml; take Xingqin Ganke granules and obtain a control solution in the same way; B. Preparation of Colorimeter Preheat the colorimeter for 30±5 minutes. After preheating, adjust the black first and then the white. C. Determination Each sample was measured three times in parallel, and L*, a*, and b* were recorded and averaged. ΔL*, Δa*, and Δb* of the test solution and the reference solution were calculated and substituted into formula (I) to calculate the ΔE* value: ΔE=(ΔL* 2 +D* 2 +Δb* 2 ) 1 / 2 (I) Wherein, ΔE: color difference value; ΔL*: brightness difference between the test solution and the reference solution; Δa*: red-green difference between the test solution and the reference solution; Δb*: yellow-blue difference between the test solution and the reference solution; D. Result judgment ΔE should be between 1.0 and 2.0; Also preferably, in step V, the sedimentation volume ratio is determined according to the following operation: Take 5g of the simulant and place it in a 50mL stoppered measuring cylinder. Add 70℃~80℃ hot water to the scale line and shake vigorously for 2 minutes. When the test sample is evenly distributed in the solution, add hot water to make the volume 50mL. After shaking evenly, read the height H0 of the suspension at this time. Let it stand for 3h, read the height H of the final sediment, and calculate the 3h sedimentation volume ratio according to H / H0; the sedimentation volume ratio should be ≥0.75; Preferably, in step V, the manual evaluation includes the following operations:

1. Recruit and screen volunteers according to the following criteria ① Sensitive sense of taste and smell, especially sensitive to sweetness, bitterness and odor; ② The subjects were aged between 20 and 50 years old; ③No drinking or smoking in the last 2 days; ④ Do not eat 2 hours before tasting the solution, especially do not eat irritating food or drink food that strongly stimulates the taste buds; 2. Preparation of test solution Take 1 bag of the simulant and 1 bag of Xingqin Ganke granules respectively, add 200 ml of 70-80°C hot water to each, stir to dissolve, and obtain the simulant test solution and the Xingqin Ganke granules test solution; prepare three portions of the simulant test solution and the Xingqin Ganke granules test solution in parallel; 3. Manual evaluation The volunteers screened in step 1 were blindly asked to taste all the simulant test solutions and the Xingqin Ganke granules test solutions, and then score the color, smell, bitterness, sweetness, sourness, saltiness and astringency of each test solution, and calculate the average score of each item; the scoring criteria are as follows: 0 points - none, 1 point - weak, mild, 2 points - moderate, 3 points - strong, 4 points - extremely strong; The average scores of the color and odor of the simulant test solution should be the same as the corresponding average scores of the Xingqin Ganke Granules test solution, and the differences in the other items should be between ±0.2.

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