Traditional Chinese medicine granule placebo and preparation method thereof

Abstract

The invention belongs to the technical field of traditional Chinese medicine particle placebo preparation, and discloses a traditional Chinese medicine particle placebo which is prepared from a medicine water extract and a medicine residue water extract. The preparation method of the medicine water extract comprises the following steps: decocting the traditional Chinese medicine raw materials twice, concentrating to obtain clear paste, carrying out alcohol precipitation, standing, filtering, and concentrating filtrate to obtain the medicine water extract. The preparation method of the decoction dreg water extract comprises the following steps: drying and frying filter residues, adding water for decoction, filtering, and concentrating filtrate. The content of the active ingredients in the traditional Chinese medicine granule placebo is lower than 10wt% of the content of the active ingredients in the corresponding medicine, and the smell is similar to that of the corresponding medicine. And the preparation process is simple and easy to industrialize.

Description

Technical Field

[0001] The present application relates to the technical field of preparation of Chinese medicine granule placebo, and in particular to a Chinese medicine granule placebo and a preparation method thereof. Background Art

[0002] Placebo refers to a type of drug preparation that has no therapeutic effect, but has a substitute and comforting effect on people who have adverse consequences from long-term use of a certain drug. With the popularization of evidence-based medicine, researchers are increasingly using placebos as controls to verify the therapeutic effects of test drugs in drug clinical trials. In clinical trials of traditional Chinese medicine, the use of qualified placebos is the key to the implementation of blind trials. The "Good Clinical Practice for Drugs" stipulates that in double-blind clinical trials, the test drugs and control drugs or placebos should be consistent in appearance, smell, packaging and other characteristics. However, in clinical research on traditional Chinese medicine, there are many difficulties in the preparation of placebos. Due to the complex composition of traditional Chinese medicine preparations and the unique taste, smell and color of natural medicines themselves, the difficulty of preparing placebos is much greater than that of chemical drugs. Especially for traditional Chinese medicine granules, the properties of both solids and aqueous solutions must be guaranteed. Summary of the invention

[0003] This application investigates the preparation methods of various Chinese medicine granule placebos, and corrects the color and taste of the placebos by adding pharmaceutical-grade and food-grade excipients, in order to provide a theoretical basis and data support for subsequent large-scale production, and to provide safe and reliable samples for clinical trials. This application provides a Chinese medicine granule placebo and a preparation method.

[0004] In a first aspect, the present application provides a Chinese medicine granule placebo, wherein the raw materials of the Chinese medicine granule placebo include a drug water extract and a drug residue water extract; The preparation method of the medicinal water extract comprises the following steps: Weighing the Chinese medicinal raw materials, adding the weighed Chinese medicinal raw materials into a container, first adding water, performing a primary decoction, filtering, second adding water to the filter residue, performing a secondary decoction, filtering, mixing the filtrates obtained after the primary decoction and the secondary decoction filtering, concentrating to obtain a clear paste, precipitating with alcohol, standing, filtering, concentrating the filtrate, and obtaining a medicinal water extract; The preparation method of the medicinal residue water extract comprises the following steps: The filter residue obtained after the secondary decoction and filtration is dried, fried, decocted with water, filtered, and the filtrate is concentrated to obtain a medicinal residue water extract. By adopting the above technical scheme, the present application adds a medicinal residue water extract and a medicinal residue water extract to the formula of a Chinese medicine granule placebo, and simultaneously adds different proportions of auxiliary materials, flavor correctors and color correctors to correct the taste and color of the placebo, so that the molding color of the granules and the taste, smell, and color of the liquid after brewing are similar to those of the Chinese medicine granule medicine, reducing the difference in appearance and smell between the test drug and the placebo, thereby eliminating the influence of psychological suggestion and expectation effect, and helping researchers to objectively evaluate the efficacy and safety of experimental drugs.

[0005] Optionally, the Chinese medicinal raw materials used in preparing the medicinal water extract of the Jinye Baidu Granule placebo are Folium Isatidis, Taraxacum Officinale and Flos Lonicerae, and the mass ratio of Folium Isatidis, Taraxacum Officinale and Flos Lonicerae is 1:1:1.

[0006] Optionally, the mass volume ratio of the total mass of the isatis indigo leaf, dandelion and honeysuckle to the amount of water added in the first water addition is 90g / L. Optionally, the mass volume ratio of the total mass of the isatis indigo leaf, dandelion and honeysuckle to the amount of water added in the second water addition is 90g / L.

[0007] Optionally, when preparing the drug water extract, the density of the clear paste is controlled to be 1.08-1.12 g / cm 3 The density of the drug water extract is controlled to be 1.30-1.38 g / cm 3 .

[0008] Optionally, the decoction time for the single decoction is 1.5-2.5h.

[0009] Optionally, the decoction time of the secondary decoction is 1.5-2.5h.

[0010] Optionally, the alcohol precipitation includes adding ethanol in an amount twice the mass of the clear paste, precipitating, taking the supernatant, and recovering the ethanol.

[0011] Optionally, when preparing the aqueous extract of the medicinal residue, the frying time is 0.5-1.5 h and the frying temperature is 150-170° C.

[0012] Optionally, the weight ratio of the drug water extract to the drug residue water extract is 1:3-8.

[0013] Optionally, in the method for preparing the medicinal residue water extract, the filtrate is concentrated to a density of 1.30-1.38 g / cm 3 .

[0014] Optionally, in the method for preparing the medicinal residue water extract, the vacuum degree of reduced pressure concentration is controlled to be (-0.1)-(-0.05) MPa, and the temperature is controlled to be 50-80°C.

[0015] Optionally, the Chinese medicine granule placebo further comprises a color corrector, and the color corrector comprises one or more of caramel pigment, sunset yellow pigment, lemon yellow pigment, β-carotene pigment and monascus red pigment.

[0016] Optionally, the Chinese medicine granule placebo further comprises a flavoring agent, and the flavoring agent comprises one or more of a bittering agent, a sour agent and a sweetening agent.

[0017] Optionally, the Chinese medicine granule placebo is Jinye Baidu Granule placebo, Huoxiang Zhengqi Granule placebo or Jiawei Ermiao Granule placebo.

[0018] Optionally, when the Chinese medicine granule placebo is the Jinye Baidu Granule placebo, the Chinese medicine raw materials used to prepare the medicinal water extract of the Jinye Baidu Granule placebo are Folium Isatidis, Taraxacum Officinale and Flos Lonicerae, and the mass ratio of Folium Isatidis, Taraxacum Officinale and Flos Lonicerae is 1:1:1.

[0019] Optionally, when the Chinese medicine granule placebo is the Jinye Baidu Granule placebo, it comprises the following raw materials in parts by weight: 100 parts of auxiliary materials, 0.8-2 parts of color correctors, 0.7-1.5 parts of flavor correctors, 0-1 parts of drug water extract and 2-3 parts of drug residue water extract.

[0020] Optionally, the auxiliary materials include 18.0 parts of powdered sugar, 0.7 parts of aspartame and 81.3 parts of dextrin.

[0021] Optionally, when the Chinese medicine granule placebo is Jinye Baidu Granule placebo, it includes the following raw materials in parts by weight: 100 parts of auxiliary materials, including 18 parts of powdered sugar, 0.7 parts of aspartame, and the balance of dextrin; 1.66 parts of color correctors, including 0.6 parts of caramel pigment, 1.0 parts of β-carotene pigment and 0.06 parts of monascus red pigment; 1.45 parts of flavoring agents, wherein the flavoring agents include 0.2 parts of DL-malic acid, 0.4 parts of citric acid, 0.6 parts of lactic acid and 0.25 parts of sucrose octaacetate; 0.5 parts of drug water extract and 2.5 parts of drug residue water extract.

[0022] Specifically, 100 g of auxiliary materials, including 18 g of powdered sugar, 0.7 g of aspartame, and the balance of dextrin; 1.66 g of color corrector, wherein the color corrector comprises 0.6 g of caramel pigment, 1.0 g of β-carotene pigment and 0.06 g of monascus red pigment; 1.45 g of flavoring agent, wherein the flavoring agent includes 0.2 g of DL-malic acid, 0.4 g of citric acid, 0.6 g of lactic acid and 0.25 g of sucrose octaacetate; 0.5g of drug water extract and 2.5g of drug residue water extract.

[0023] In the second aspect of the present application, the present application provides a method for preparing the Chinese medicine granule placebo described in the first aspect of the present application, comprising the following steps: adjusting the ratio of the drug water extract and the drug residue water extract so that the content of the active ingredient in the placebo is lower than 10wt% of the content of the active ingredient in the corresponding drug, and the smell is similar to that of the corresponding drug.

[0024] Optionally, the method for preparing the Chinese medicine granule placebo further comprises the following steps: S1. Mix and stir the auxiliary materials, color correctors, flavor correctors, aqueous extracts of drug residues and aqueous extracts of drugs to obtain a soft material; S2, granulating the soft material obtained in step S1, drying, and granulating to obtain the Chinese medicine granule placebo.

[0025] In summary, the present invention includes at least one of the following beneficial technical effects: 1. The present application adds a drug water extract and a drug residue water extract to the formula of a traditional Chinese medicine granule placebo, and adjusts the ratio of the drug water extract and the drug residue water extract, so that the content of the active ingredient in the placebo is lower than 10wt% of the content of the active ingredient in the corresponding drug, and the smell is similar to that of the corresponding drug; 2. The present application corrects the color of the Chinese medicine granule placebo by adding edible pigments in different proportions, so that the molding color of the granules and the color of the liquid after brewing are similar to those of the Chinese medicine granules; and by adding flavoring agents in different proportions, it produces a smell and taste similar to those of the Chinese medicine granules. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 A color appearance comparison diagram of the solid particles and aqueous solution of the Jinye Baidu Granule placebo and the Jinye Baidu Granule drug sample prepared in Examples 1-4; in, Figure 1 A represents the appearance of the Jinye Baidu Granules placebo and Jinye Baidu Granules prepared in Examples 1, 2, 3, and 4, respectively. The Jinye Baidu Granules placebo and Jinye Baidu Granules prepared in Examples 1, 2, 3, and 4 correspond to No. 1, No. 2, No. 3, No. 4, and No. 5, respectively; Figure 1 B represents the appearance of the Jinye Baidu Granule placebo and the Jinye Baidu Granule solution prepared into 10 g / 100 ml prepared in Examples 1, 2, 3, and 4, respectively. The Jinye Baidu Granule placebo and the Jinye Baidu Granule solution prepared in Examples 1, 2, 3, and 4 correspond to No. 1, No. 2, No. 3, No. 4, and No. 5, respectively; Figure 2 This is a radar chart of electronic tongue measurement of the Jinye Baidu Granule placebo prepared in Example 1; Figure 3 HPLC chromatograms of chlorogenic acid in different samples; in, Figure 3 A is the HPLC chromatogram of the Jinye Baidu Granule placebo prepared in Example 1; Figure 3 B is the HPLC chromatogram of Jinye Baidu Granules; Figure 3 C is the HPLC chromatogram of chlorogenic acid reference substance. DETAILED DESCRIPTION

[0027] The present application designs a method for preparing a Chinese medicine granule placebo, wherein the raw materials of the Chinese medicine granule placebo include a drug water extract and a drug residue water extract; The present application is further described in detail below with reference to the accompanying drawings and specific embodiments.

[0028] Example 1-16: Jinye Baidu Granule Placebo The preparation methods of the drug water extract and the drug residue water extract used in Examples 1-16 are as follows: The preparation method of the drug water extract comprises the following steps: Take 300g of Isatis indigofera, 300g of dandelion and 300g of honeysuckle, add 10L of water, decoct once, decoct for 2h, filter out with a 200-mesh filter, add 10L of water to the dregs after the first decoction, decoct for a second time, decoct for 2h, filter out with a 200-mesh filter, mix the decoctions obtained from the first decoction and the second decoction, control the temperature to 60°C, the vacuum degree to -0.1MPa, and concentrate under reduced pressure to a density of 1.10g / cm 3 , and obtain a clear paste. Add ethanol twice the mass of the clear paste to precipitate. Take the supernatant, recover the ethanol, let it stand overnight, filter, and concentrate the filtrate to a density of 1.35 g / cm 3 , and obtain the medicinal water extract (162g).

[0029] The preparation method of the medicinal residue water extract comprises the following steps: The drug residue filtered out after the second decoction in the preparation process of the above-mentioned drug water extract was collected, dried at 70°C for 30 hours, and the dried drug residue was fried in a frying pan at a frying temperature of 160°C for 60 minutes. Then, the fried drug residue was added to a decoction container, 10L of water was added, and decocted. The decoction was boiled for 1.5 hours, and filtered out with a 200-mesh filter. The filtrate was the drug residue extract. The filter residue was added with 10L of water and decocted. The decoction was boiled for 1.5 hours, and filtered out with a 200-mesh filter. The filtrate was the drug residue extract. The two drug residue extracts were combined, the temperature was controlled at 60°C, the vacuum degree was -0.1MPa, and the drug residue was concentrated under reduced pressure to a relative density of 1.35g / cm 3 , and obtained the water extract of the residue (169.2g).

[0030] The Jinye Baidu Granule sample used in Examples 1-16 is Jinye Baidu Granule (Sinopharm Group Zhonglian Pharmaceutical Co., Ltd., approval number Z20040020).

[0031] Examples 1-4 Examples 1-4 are Jinye Baidu Granule placebos made with different raw material ratios, the difference being that the color correcting agent ratios are different, as follows: The Jinye Baidu Granule placebo in Example 1 comprises the following raw materials in parts by weight: 100 g of auxiliary materials, including 18.0 g of powdered sugar, 0.7 g of asparagus and the remainder of dextrin; 0.5g of Jinye Baidu Granules drug water extract and 2.5g of drug residue water extract; 1.66g color corrector; the color corrector includes 0.6g edible caramel pigment, 1.0g edible β-carotene pigment, and 0.06g edible monascus red pigment; 1.45 g of flavoring agent, the flavoring agent includes 0.2 g of DL-malic acid, 0.4 g of citric acid, 0.6 g of lactic acid and 0.25 g of sucrose octaacetate.

[0032] Example 2 is based on Example 1, with the difference that the color corrector in Example 2 includes 0.5 g of edible caramel pigment, 1.2 g of edible β-carotene pigment, and 0.1 g of edible monascus red pigment.

[0033] Example 3 is based on Example 1, with the difference that the color corrector in Example 3 includes 0.8 g of edible caramel pigment, 1.0 g of edible β-carotene pigment, and 0.1 g of edible monascus red pigment.

[0034] Example 4 is based on Example 1, except that the color corrector in Example 4 includes 0.8 g of edible caramel pigment, 1.0 g of edible β-carotene pigment, and 0.6 g of edible monascus red pigment.

[0035] The preparation method of the Jinye Baidu Granule placebo in Examples 1-4 comprises the following steps: S1, dissolving DL-malic acid, citric acid, lactic acid, edible caramel pigment, edible β-carrot pigment, and edible red monascus pigment in water to obtain corresponding aqueous solutions, wherein DL-malic acid aqueous solution (0.1 g / ml), citric acid aqueous solution (0.1 g / ml), lactic acid aqueous solution (0.1 g / ml), edible caramel pigment aqueous solution (0.1 g / ml), edible β-carrot pigment aqueous solution (0.1 g / ml), and edible red monascus pigment aqueous solution (0.05 g / ml) are set aside; dissolving octaacetic acid sucrose lipid in 50wt% ethanol aqueous solution, octaacetic acid sucrose lipid solution (0.1 g / ml), set aside; S2, placing powdered sugar, asparagus sugar, dextrin, Jinye Baidu Granules drug water extract and drug residue water extract in a mixer, stirring, adding all the materials prepared in step S1, stirring until the mixed materials have a uniform color, and preparing a soft material; S3, placing the soft material in a swing granulator, passing through a 14-mesh sieve to obtain wet granules, drying at 60°C, and granulating the dried granules using a sieve with an upper sieve of 12 mesh and a lower sieve of 40 mesh to obtain granules with uniform particle size; S4, dissolve 4.3uL of Houttuynia cordata oil in an equal volume of anhydrous ethanol, spray evenly into the granules with a spray bottle, set the speed of a cone mixer to 8r / min, mix for 20min, and prepare Jinye Baidu Granules placebo; The color, appearance and shape of the Jinye Baidu Granule placebo prepared in Examples 1-4 were compared with the Jinye Baidu Granule drug sample. Figure 1 ; The Jinye Baidu Granules placebo and Jinye Baidu Granules drug samples prepared in Examples 1-4 were respectively dissolved according to the solubility requirements of granules in the Chinese Pharmacopoeia (2020) to obtain placebo granule solutions and drug sample solutions with different prescription amounts, with a concentration of 10 g / 100 ml. The color, appearance and shape were compared. See Figure 1 .

[0036] like Figure 1 As shown, Figure 1 The appearance of particles No. 1, No. 2, No. 3 and No. 4 in A respectively corresponds to the appearance of particles of the Jinye Baidu Granule placebo prepared in Example 1, Example 2, Example 3 and Example 4, Figure 1 The number 5 in A corresponds to the appearance of the Jinye Baidu Granules; Figure 1 The appearance of particles No. 1, No. 2, No. 3 and No. 4 in B respectively corresponds to the appearance of the solution of the Jinye Baidu Granule placebo prepared in Example 1, Example 2, Example 3 and Example 4, Figure 1 Number 5 in B corresponds to the appearance of the solution of the Jinye Baidu Granules drug.

[0037] Will Figure 1 A particles and Figure 1 By comparing the solutions in B, it can be seen that the color and appearance properties of the Jinye Baidu Granules placebo granules and solution in No. 1 are most similar to those of No. 5 (Jinye Baidu Granules). Therefore, the granule appearance and solution appearance of the Jinye Baidu Granules placebo prepared in Example 1 are closest to the appearance of the Jinye Baidu Granules drug sample.

[0038] Chroma calculation and evaluation of granules The chromaticity of the Jinye Baidu Granules placebo granules and the Jinye Baidu Granules drug sample prepared in Example 1 was measured respectively, and the color difference was calculated: The color evaluation index ΔE calculated using the CIE-Lab color difference formula can better reflect the color difference between the standard sample and the test sample, and also meet the human visual organ's perception of color changes.

[0039] The determination process includes the following steps: T1. Calibrate the colorimeter. Calibrate the same set of samples once. Use a standard blackboard for 0 calibration and a standard white board for 100% calibration. T2. Each sample was measured three times in parallel. During the measurement, a colorimeter was used to measure and record the L value, a value, and b value, and the ΔE (color difference) was calculated. The specific calculation formula is as follows: In the formula, a* represents the chromaticity range between red and green, b* represents the chromaticity range between yellow and blue; the values ​​of a* and b* are between -120 and 120, and L* represents the brightness of the color, with a value between 0 and 100.

[0040] L1*, a1*, and b1* represent the L value, a value, and b value of the placebo, and L0*, a0*, and b0* represent the L value, a value, and b value of the placebo.

[0041] The measurement results of the color difference ΔE are shown in Table 1, and the evaluation index of the color difference ΔE is shown in Table 2.

[0042] Table 1 Chromatographic determination results of Jinye Baidu Granules and placebo Table 2 Color difference perception ΔE Visual color difference 0～0.5 Slight color difference 0.5～1.5 Small color difference 1.5～3 Small color difference 3～6 Large color difference Combining the analysis of Table 1 and Table 2, it can be seen that the ΔE value of the Jinye Baidu Granules placebo granules and the Jinye Baidu Granules drug sample prepared in Example 1 is 1.34. When ΔE is in the range of 0.5 to 1.5, the color difference between the samples is small.

[0043] Therefore, when the formula of the color corrector is 0.6g of edible caramel color, 1.0g of edible β-carotene color, and 0.06g of edible monascus red pigment; the color of the placebo granules prepared by this prescription is similar to that of Jinye Baidu Granules, and the simulation effect is better.

[0044] Embodiment 5-10 Examples 5-10 are Jinye Baidu Granule placebos made with different raw material ratios. Examples 5-11 are based on Example 1, except that the dosages of the drug water extract and the drug residue water extract are different, as follows: Example 5 is based on Example 1, except that the dosage of the drug water extract in Example 5 is 3 g, and no drug residue water extract is added in Example 5.

[0045] Example 6 is based on Example 1, with the difference that the amount of the drug water extract in Example 6 is 2.5 g, and the amount of the drug residue water extract is changed to 0.5 g.

[0046] Example 7 is based on Example 1, with the difference that the amount of the drug water extract in Example 7 is 2 g, and the amount of the drug residue water extract is changed to 1 g.

[0047] Example 8 is based on Example 1, with the difference that the amount of the drug water extract in Example 8 is 1.5 g, and the amount of the drug residue water extract is changed to 1.5 g.

[0048] Example 9 is based on Example 1, with the difference that the amount of the drug water extract in Example 9 is 1 g, and the amount of the drug residue water extract is changed to 2.0 g.

[0049] Example 10 is based on Example 1, except that: in Example 10, no Jinye Baidu Granule drug water extract is added, and the amount of drug residue water extract is changed to 3.0 g.

[0050] The Jinye Baidu Granules placebo prepared in Example 1 and Examples 5-10 were subjected to an olfactory manual evaluation test: 8 judges with a sensitive sense of smell were recruited to manually score the odor of the Jinye Baidu Granules placebo prepared in the above different examples. Referring to the scoring criteria in Table 3, the results were analyzed for significance using SPSS27.0 software, and the results are shown in Table 4.

[0051] Table 3 Odor rating criteria for Jinye Baidu Granules placebo Table 4 Human evaluation results of the odor of Jinye Baidu Granules (X±SD, n=8) Note: Different letters in the superscripts indicate significant differences (P<0.05) Combining the analysis of Table 3 and Table 4, it can be seen that the scores of Example 1 and Example 10 are significantly higher than those of the other groups, among which the manual evaluation score in Example 1 is the highest at 91.5±6.3. Therefore, the placebo prepared in Example 1 is closest to Jinye Baidu Granules in the artificial olfactory evaluation. Therefore, the Jinye Baidu Granules placebo prepared in Example 1 was selected for subsequent olfactory similarity analysis.

[0052] Olfactory similarity analysis The Jinye Baidu Granule placebo prepared in Example 1 was tested using an electronic nose. 5 g of the Jinye Baidu Granule placebo prepared in Example 1 was taken and allowed to stand for 1 hour at room temperature before testing. The electronic nose set parameters: sampling interval, detection time 60 s, cleaning time 120 s, injection speed 300 ml / min, 10 sensors W1C, W5S, W3C, W6S, W5C, W1S, W1W, W2S, W2W, W3S were selected, each sample was collected 3 times, and the cosine similarity (COS) was calculated with the help of Matlab-2017a software. The test results are shown in Table 5.

[0053] Table 5 Electronic nose measurement results Analysis of Table 2 shows that the cosine similarity between the two groups of data calculated by Matlab-2017a software is 99.89%, which shows that the Jinye Baidu Granules placebo prepared in Example 1 and the Jinye Baidu Granules drug sample have good olfactory similarity.

[0054] Comparative Examples 1-4 Comparative Example 1 The difference between Comparative Example 1 and Example 1 is that the decoction is performed only once.

[0055] The preparation method of the Jinyebaidu water extract comprises the following steps: Take 300g of Isatis indigofera, 300g of dandelion and 300g of honeysuckle, add 20L of water, decoct for 4h, filter with a 200-mesh filter, control the temperature to 60℃, the vacuum degree to -0.1MPa, and concentrate under reduced pressure to a relative density of 1.35g / cm 3 , and the water extract of Jinye Baidu Granules was prepared.

[0056] The preparation method of the medicinal residue water extract comprises the following steps: The drug residue filtered out after decoction in the preparation process of the above-mentioned Jinye Baidu water extract was collected, dried at 70°C for 30 hours, and the dried drug residue was fried in a frying pan at a frying temperature of 160°C for 60 minutes. Then, the fried drug residue was added to a decoction container, 10L of water was added, and decocted. The decoction was boiled for 1.5 hours, and filtered out with a 200-mesh filter. The filtrate was the drug residue extract; 10L of water was added to the filter residue, and the decoction was boiled for 1.5 hours. The filter residue was filtered out with a 200-mesh filter. The filtrate was the drug residue extract. The two drug residue extracts were combined, the temperature was controlled at 60°C, the vacuum degree was -0.1MPa, and the drug residue was concentrated under reduced pressure to a relative density of 1.35g / cm 3 , and obtain the water extract of the residue.

[0057] The Jinye Baidu Granules placebo prepared in Comparative Example 1 was tested using an electronic nose, and the results are shown in the following table: Table 5-1 Comparative Example 2 The difference between Comparative Example 2 and Example 1 is that the preparation method of the aqueous extract of medicinal residues does not include a frying step.

[0058] The preparation method of the medicinal residue water extract comprises the following steps: The drug residue filtered out after the second decoction in the preparation process of Jinye Baidu water extract was collected and dried at 70°C for 30 hours. The dried drug residue was added to a decoction container, 10L of water was added, and the decoction was performed. The decoction was performed under boiling conditions for 1.5 hours, and the filtrate was filtered out with a 200-mesh filter. The filtrate was the drug residue extract. The filter residue was added with 10L of water and decocted. The decoction was performed under boiling conditions for 1.5 hours, and the filtrate was filtered out with a 200-mesh filter. The filtrate was the drug residue extract. The two drug residue extracts were combined, the temperature was controlled at 60°C, the vacuum degree was -0.1MPa, and the drug residue was concentrated under reduced pressure to a relative density of 1.35g / cm 3 , and obtain the water extract of the residue.

[0059] The Jinye Baidu Granules placebo prepared in Comparative Example 2 was tested using an electronic nose, and the results are shown in the following table: Table 5-2 Comparative Example 3 The difference between Comparative Example 3 and Example 1 is that in the preparation method of the aqueous extract of the medicinal residue, the aqueous extract is concentrated under reduced pressure to a relative density of 1.20 g / cm 3 .

[0060] The Jinye Baidu Granules placebo prepared in Comparative Example 3 was tested using an electronic nose, and the results are shown in the following table: Table 5-3 Comparative Example 4 The difference between Comparative Example 4 and Example 1 is that in the preparation method of the aqueous extract of the medicinal residue, the aqueous extract is concentrated under reduced pressure to a relative density of 1.49 g / cm 3 .

[0061] The Jinye Baidu Granules placebo prepared in Comparative Example 4 was tested using an electronic nose, and the results are shown in the following table: Table 5-4 Examples 11-16 Examples 11-16 are Jinye Baidu Granule placebos made with different raw material ratios, the difference being that the ratios of flavor correctives are different, as follows: Example 11 is based on Example 1, except that the flavoring agent in Example 11 includes 0.1 g DL-malic acid, 0.1 g citric acid, 0.1 g lactic acid and 0.1 g sucrose octaacetate.

[0062] Example 12 is based on Example 1, except that the flavoring agent in Example 12 includes 0.2 g DL-malic acid, 0.2 g citric acid, 0.2 g lactic acid and 0.15 g sucrose octaacetate.

[0063] Example 13 is based on Example 1, except that the flavoring agent in Example 13 includes 0.2 g DL-malic acid, 0.4 g citric acid, 0.4 g lactic acid and 0.2 g sucrose octaacetate.

[0064] Example 14 is based on Example 1, except that the flavoring agent in Example 14 includes 0.4 g DL-malic acid, 0.4 g citric acid, 0.6 g lactic acid and 0.3 g sucrose octaacetate.

[0065] Example 15 is based on Example 1, except that the flavoring agent in Example 15 includes 0.6 g DL-malic acid, 0.4 g citric acid, 0.6 g lactic acid and 0.35 g sucrose octaacetate.

[0066] Example 16 is based on Example 1, except that the flavoring agent in Example 16 includes 0.6 g DL-malic acid, 0.6 g citric acid, 0.6 g lactic acid and 0.4 g sucrose octaacetate.

[0067] The Jinye Baidu Granule placebos prepared in Example 1 and Examples 11-16 were manually evaluated, and the evaluation results are shown in Table 6.

[0068] Table 6 Results of manual evaluation of the taste of the Jinye Baidu Granules placebo Example Human evaluation Embodiment 11 The sour and bitter taste is weak and the medicinal taste is inconsistent; Example 12 Slightly sour, slightly bitter, and medicinal; Embodiment 13 Slightly sour and bitter, the taste is basically similar to that of other medicines; Example 1 Moderately sour, moderately bitter, and medicinal-like; Embodiment 14 Too much sourness, too much bitterness, the taste of the medicine is different; Embodiment 15 Too much sourness, too much bitterness, and a big difference in medicinal taste; Example 16 Too much sourness, too much bitterness, and a big difference in medicinal taste; According to the manual evaluation results in Table 6, the placebo granules in Example 1 tasted consistent with the test drug, had a good simulation effect, and a subsequent taste similarity analysis was performed.

[0069] Taste similarity analysis The electronic tongue was used to analyze the taste similarity between the Jinye Baidu Granule placebo and the Jinye Baidu Granule drug sample prepared in Example 1. 5 g of each was taken, dissolved and filtered with ultrapure water to 50 mL, balanced at room temperature for 1 hour, and tested. Detection parameters: sampling interval 1 second, the taste sensor and ceramic reference electrode were cleaned for a total of 240 seconds, balanced for 30 seconds, sample measurement for 30 seconds, aftertaste measurement for 30 seconds, the value after the sensor signal stabilized was selected, and each sample was collected 3 times. The measurement results are shown in Figure 2 right Figure 2 Analysis shows that the astringency and saltiness data of the Jinye Baidu Granules placebo prepared in Example 1 on the sensor are slightly higher than those of the Jinye Baidu Granules, and the response intensities of the two on other sensors are comparable; in general, the taste similarity between the Jinye Baidu Granules placebo prepared in Example 1 and the Jinye Baidu drug granules sample is relatively high.

[0070] Determination of active ingredient content Drugs used in clinical trials of new Chinese medicines should comply with the relevant requirements of the Appendix to the Good Manufacturing Practice for Pharmaceuticals for Clinical Trials and the Good Clinical Practice for Pharmaceuticals. According to relevant regulations, placebos should not interfere with the observation and evaluation of the safety and effectiveness of the test drugs. Relevant regulations point out that in placebo preparation studies, 1 / 20 to 1 / 10 of the effective dose of the prescription drug can be added to make the appearance, taste and smell of the placebo more similar to the test drug. Therefore, the content of the active ingredient in the placebo should meet the requirements so as not to interfere with the test results.

[0071] It is known that chlorogenic acid in the Jinye Baidu drug granules is one of its main active ingredients.

[0072] The chlorogenic acid content in the Jinye Baidu Granules and the Jinye Baidu Granules placebo prepared in Example 1 was determined respectively according to the high performance liquid chromatography method (General Rule 0512) of the 2020 edition of the "Chinese Pharmacopoeia".

[0073] The measurement parameters are as follows: Octadecylsilane bonded silica gel was used as filler, acetonitrile-water-glacial acetic acid (6:92:2) was used as mobile phase, and the detection wavelength was 327 nm. The theoretical plate number calculated based on the chlorogenic acid peak should be no less than 4000.

[0074] Preparation of reference solution: Take an appropriate amount of chlorogenic acid reference substance, weigh it accurately, place it in a brown volumetric flask, and add 40% methanol to make a solution containing 3 μg per 1 ml.

[0075] Preparation of test solution: Take the product under the item of filling amount difference, grind it, take 0.5g, weigh it accurately, put it in a 50ml brown volumetric bottle, add an appropriate amount of 40% methanol, ultrasonically treat it (power 200W, frequency 40kHz) for 20 minutes, let it cool to room temperature, add 40% methanol to the scale, shake it well, filter it, take the filtrate, and accurately take 20μl of the reference solution and the test solution, inject it into the liquid chromatograph, and measure it. The measurement results are shown in Table 7 and Figure 3 .

[0076] Table 7 Determination results of chlorogenic acid content in different samples sample Peak area (mAU*s) Concentration (mg / ml) Content (mg / g) Chlorogenic acid reference substance 1613.80 0.0289 / Jinye Baidu Granules 2636.57 0.0472 4.69 Jinye Baidu Granules Placebo 213.87 0.0038 0.38 like Figure 3 As shown, Figure 3 In Figure 3 A. Figure 3 B. Figure 3 C corresponds to the HPLC chromatograms of the Jinye Baidu Granules placebo, the Jinye Baidu Granules drug sample and the chlorogenic acid reference substance prepared in Example 1, respectively. Figure 3 In the experiment, the Jinye Baidu Granules placebo, the Jinye Baidu Granules drug sample and the chlorogenic acid reference substance all peaked between 20 and 25 minutes, and the peak shape was good. The peak area and concentration content corresponding to the peak shape are shown in Table 7. It was calculated from the data in Table 7 that the chlorogenic acid content of the Jinye Baidu Granules drug sample was 4.69 mg / g, and the chlorogenic acid content of the placebo prepared in Example 1 was 0.38 mg / g. The chlorogenic acid content in the latter was lower than 10% of the former, which met the requirements for clinical placebo.

[0077] The above are all preferred embodiments of the present application, and the protection scope of the present application is not limited thereto. Therefore, any equivalent changes made according to the structure, shape, and principle of the present application should be included in the protection scope of the present application.

Claims

1. A Chinese medicine granule placebo, characterized in that: The raw materials of the Chinese medicine granule placebo include drug water extract and drug residue water extract; The preparation method of the medicinal water extract comprises the following steps: Weighing the Chinese medicinal raw materials, adding the weighed Chinese medicinal raw materials into a container, first adding water, performing a primary decoction, filtering, second adding water to the filter residue, performing a secondary decoction, filtering, mixing the filtrates obtained after the primary decoction and the secondary decoction filtering, concentrating to obtain a clear paste, precipitating with alcohol, standing, filtering, concentrating the filtrate, and obtaining a medicinal water extract; The preparation method of the medicinal residue water extract comprises the following steps: The filter residue obtained after the secondary decoction and filtration is dried, fried, decocted with water, filtered, and the filtrate is concentrated to obtain the medicinal residue water extract.

2. The Chinese medicine granule placebo according to claim 1, characterized in that: The weight ratio of the drug water extract to the drug residue water extract is 1:3-8.

3. The Chinese medicine granule placebo according to claim 1, characterized in that: In the preparation method of the medicinal residue water extract, the filtrate is concentrated to a density of 1.30-1.38 g / cm 3 .

4. The Chinese medicine granule placebo according to claim 1, characterized in that: In the method for preparing the medicinal residue water extract, the vacuum degree of reduced pressure concentration is controlled to be (-0.1)-(-0.05) MPa, and the temperature is controlled to be 50-80°C.

5. The Chinese medicine granule placebo according to claim 1, characterized in that: The Chinese medicine granule placebo also includes a color corrector, which includes one or more of caramel pigment, sunset yellow pigment, lemon yellow pigment, β-carotene pigment and monascus red pigment; the Chinese medicine granule placebo also includes a flavor corrector, which includes one or more of bittering agents, sour agents and sweeteners.

6. The Chinese medicine granule placebo according to any one of claims 1 to 5, characterized in that: The Chinese medicine granule placebo is Jinye Baidu granule placebo, Huoxiang Zhengqi granule placebo or Jiawei Ermiao granule placebo.

7. The Chinese medicine granule placebo according to claim 6, characterized in that: When the Chinese medicine granule placebo is the Jinye Baidu Granule placebo, the Chinese medicine raw materials used to prepare the medicinal water extract of the Jinye Baidu Granule placebo are Isatis indigotica, Taraxacum officinale and Honeysuckle, and the mass ratio of the Isatis indigotica, Taraxacum officinale and Honeysuckle is 1:1:

1.

8. The Chinese medicine granule placebo according to claim 6, characterized in that: When the Chinese medicine granule placebo is Jinye Baidu granule placebo, it comprises the following raw materials in parts by weight: 100 parts of auxiliary materials, 0.8-2 parts of color correctors, 0.7-1.5 parts of flavor correctors, 0-1 parts of drug water extract and 2-3 parts of drug residue water extract.

9. A method for preparing the Chinese medicine granule placebo according to any one of claims 1 to 8, characterized in that: The method comprises the following steps: adjusting the ratio of the drug water extract and the drug residue water extract so that the content of the active ingredient in the placebo is lower than 10wt% of the content of the active ingredient in the corresponding drug, and the smell is similar to that of the corresponding drug.

10. The method for preparing the Chinese medicine granule placebo according to claim 9, characterized in that: The following steps are also included: S1. Mix and stir the auxiliary materials, color correctors, flavor correctors, aqueous extracts of drug residues and aqueous extracts of drugs to obtain a soft material; S2, granulating the soft material obtained in step S1, drying, and granulating to obtain the Chinese medicine granule placebo.

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