Donkey-hide gelatin compound oral liquid placebo and preparation method thereof

Abstract

The invention relates to the field of medicines, in particular to a donkey-hide gelatin compound oral liquid placebo and a preparation method thereof. The colla corii asini compound oral liquid placebo comprises colla corii asini compound oral liquid raw medicine, coffee essence, scorched essence, a sour agent, a sweetening agent, a bitter agent, a thickening agent, pigment and optional water, and preferably comprises colla corii asini compound oral liquid raw medicine, coffee essence, scorched essence, mature vinegar, rock candy, sucrose octaacetate, soluble starch and caramel pigment. And optionally water. The colla corii asini compound oral liquid placebo is similar to a test medicine colla corii asini compound oral liquid in the aspects of appearance, color, taste, smell and the like, and can be used for preventing blurring to the greatest extent, so that smooth proceeding of a clinical test is ensured.

Description

Technical Field

[0001] The present invention relates to the field of medicine, and in particular to a placebo of donkey-hide gelatin compound oral liquid and a preparation method thereof. Background Art

[0002] A placebo is a simulated drug that contains no or minimal pharmacologically active ingredients, has no therapeutic effect on the observed physiological or pathological phenomenon, and is identical or similar to the test drug in appearance, taste, and smell. A placebo is essentially a "sham" treatment designed to eliminate psychological bias in researchers and subjects and to demonstrate the absolute effectiveness and safety of the test drug.

[0003] In recent years, with the release of a series of policy documents supporting the development of new TCM drugs, the number of TCM drug development projects has rapidly increased, and the importance of TCM placebos in this area has become increasingly prominent. However, compared to chemical drugs, TCM has a variety of medicinal flavors and complex ingredients, making the preparation of TCM placebos significantly more difficult. Simulating the appearance, odor, and taste of TCM preparations remains a major challenge in the development of TCM placebos.

[0004] Donkey-hide gelatin compound oral liquid is made by combining the precious animal medicinal material donkey-hide gelatin with four botanical medicinal materials: red ginseng, codonopsis, hawthorn, and prepared rehmannia. It is widely used to treat symptoms such as qi and blood deficiency, palpitations, insomnia, and leukopenia, and is currently attracting much attention in clinical research. However, in the field of placebo preparation, simulation of donkey-hide gelatin compound oral liquid has not yet been reported. Although research on traditional Chinese medicine placebos has made some progress, most studies focus on pure botanicals, and the preparation technology for compound preparations containing animal medicinal materials is still immature. Furthermore, the unique smell of donkey-hide gelatin, coupled with the complex taste of various botanicals, results in a multi-layered smell and taste, making simulation difficult. Existing technologies for taste and odor simulation have certain limitations, primarily relying on the addition of low doses of the original drug, sweeteners, or bittering agents. This method is more suitable for the preparation of placebos for chemical drugs and is more prone to blinding for traditional Chinese medicines, especially compound preparations such as donkey-hide gelatin compound oral liquid that contain both botanical and animal medicinal materials.

[0005] To this end, in response to existing technical problems and the characteristics of donkey-hide gelatin compound oral liquid, a placebo preparation method was developed that can simulate its unique taste and smell without interfering with the efficacy evaluation, which is of great significance for the efficacy evaluation of donkey-hide gelatin compound oral liquid. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to provide a placebo of donkey-hide gelatin compound oral liquid and a preparation method thereof. The placebo of donkey-hide gelatin compound oral liquid is similar to the experimental drug donkey-hide gelatin compound oral liquid in appearance, color, taste, smell, etc., and can minimize the risk of blinding, thereby ensuring the smooth progress of clinical trials.

[0007] In order to achieve the above technical objectives, the technical solution adopted by the present invention is:

[0008] A placebo of donkey-hide gelatin compound oral liquid comprises the original donkey-hide gelatin compound oral liquid, flavor, acidulant, sweetener, bittering agent, thickener and pigment, and optionally water; the flavor comprises coffee flavor and caramel flavor.

[0009] The amount of the original medicine added to the donkey-hide gelatin compound oral liquid is 2-10% (the weight ratio of the total weight of the donkey-hide gelatin compound oral liquid placebo), such as 2, 3, 4, 5, 6, 7, 8, 9, 10%, preferably 5%.

[0010] Because the donkey-hide gelatin compound oral liquid has multiple flavors, including the burnt aroma and bitterness of gelatinous and botanical herbs, and contains Maillard reaction-like products and complex volatile components, giving it a rich odor layer, a compound flavor with multiple layers of aroma and taste was selected; the compound flavor is composed of coffee flavor and caramel flavor. The coffee flavor is added in an amount of 0.6% to 1.8% of the total weight, preferably 1.2% of the total weight; the caramel flavor is added in an amount of 0.5% to 1.5% of the total weight, preferably 1% of the total weight.

[0011] In order to solve the multi-layered nature of the smell, the essence is prepared by combining the Maillard reaction with the blending of typical aroma substrates.

[0012] Furthermore, the method for preparing the coffee essence includes the following steps: fully mixing soy protein isolate with water, adding protease for enzymatic hydrolysis, then inactivating the enzyme, and filtering to obtain a protein hydrolyzate; preparing the protein hydrolyzate, coffee bean powder, reducing sugar, and combined amino acids, and mixing them evenly; adjusting the pH of the solution to about 7; subjecting the mixed solution to a Maillard reaction, and sieving the reaction product to obtain the coffee essence.

[0013] Specifically, soy protein isolate and water (preferably purified water) are fully mixed in a mass ratio of 1:1-5, preferably 1:3. Protease is added at 50-70°C, such as 60°C, and enzymatic hydrolysis is carried out for 0.5-3h, such as 1h, followed by high-temperature enzyme inactivation at 80-100°C for 5-20min, such as 90°C for 10min. The reducing sugar comprises glucose and fructose, and the mass ratio of the two is 1-5:2, preferably 3:2. The combined amino acids comprise cysteine, arginine, lysine and aspartic acid, and the mass ratio is 1:(1-2):(1-2):1, preferably 1:2:2:1. The mass ratio of protein hydrolyzate, coffee bean powder, reducing sugar and combined amino acids is (15-25):3:(15-20):3, preferably 20:3:20:3. A buffer solution is used to adjust the pH, such as a citric acid-sodium citrate buffer solution. The Maillard reaction is carried out by heating the reaction at 80-100° C. for 1-3 hours, preferably at 90° C. for 2 hours. The reaction product is sieved through a 20-60 mesh sieve, preferably a 40 mesh sieve.

[0014] Preferably, the preparation method of the coffee essence comprises the following steps: fully mixing soy protein isolate and water in a mass ratio of 1:1-5, adding protease and performing enzymatic hydrolysis at 50-70°C for 0.5-3h, then adjusting the temperature to 80-100°C to inactivate the enzyme for 5-20min, and filtering to obtain a protein hydrolyzate; preparing the protein hydrolyzate, coffee bean powder, reducing sugar, and combined amino acids, and uniformly mixing them in a ratio of (15-25):3:(15-20):3, wherein the reducing sugar composition and ratio are glucose:fructose=1-5:2, and the combined amino acid composition and ratio are cysteine:arginine:lysine:aspartic acid=1:(1-2):(1-2):1; adjusting the pH of the solution to 7 using a buffer solution; heating the mixed solution at 80-100°C for 1-3h to perform a Maillard reaction, and filtering the reaction product through a 20-60 mesh sieve to obtain the coffee essence.

[0015] More preferably, the method for preparing the coffee essence comprises the following steps: fully mixing soy protein isolate and water in a mass ratio of 1:3, adding protease for enzymatic hydrolysis at 60°C for 1 hour, then adjusting the temperature to 90°C for high-temperature enzyme inactivation for 10 minutes, and filtering to obtain a protein hydrolyzate; preparing the protein hydrolyzate, coffee bean powder, reducing sugar, and combined amino acids, and uniformly mixing them in a ratio of 20:3:20:3, wherein the reducing sugar composition and ratio are glucose:fructose = 3:2, and the combined amino acid composition and ratio are cysteine:arginine:lysine:aspartic acid = 1:2:2:1; using citric acid-sodium citrate buffer to adjust the pH of the solution to 7; heating the mixed solution at 90°C for 2 hours to carry out a Maillard reaction, and passing the reaction product through a 40-mesh sieve to obtain the essence.

[0016] Furthermore, the preparation method of the caramel flavor comprises the following steps: mixing propylene glycol, vanillin, vanillin propylene glycol acetal, methylcyclopentenolone, and maltol, and heating and stirring until the mixture is completely dissolved.

[0017] Specifically, the mass ratio of propylene glycol, vanillin, vanillin propylene glycol acetal, methylcyclopentenolone, and maltol is (40-120): (2-8): (0.5-2): (0.5-2): 0.1, preferably 80: 4: 1: 1: 0.1. The mixture is heated and stirred at 40-60°C, preferably at 50°C.

[0018] Preferably, the preparation method of the caramel flavor comprises the following steps: mixing propylene glycol, vanillin, vanillin propylene glycol acetal, methylcyclopentenolone, and maltol in a mass ratio of (40-120): (2-8): (0.5-2): (0.5-2): 0.1, and heating and stirring at 40-60°C until completely dissolved.

[0019] More preferably, the preparation method of the caramel flavor comprises the following steps: mixing propylene glycol, vanillin, vanillin propylene glycol acetal, methylcyclopentenolone, and maltol in a mass ratio of 80:4:1:1:0.1, and heating and stirring at 50°C until completely dissolved.

[0020] According to the analysis of professional sensory evaluators, the taste of donkey-hide gelatin compound oral liquid is mainly divided into three levels: sour, sweet and bitter. Therefore, foods or food additives with corresponding taste attributes and no specific activity are selected as flavor enhancers.

[0021] Furthermore, the acidulant is aged vinegar with a sour and mellow taste; the added amount of the aged vinegar is 1% to 3% of the total mass, preferably 2% of the total mass.

[0022] Furthermore, the sweetener is at least one of xylitol, sorbitol, maltitol and rock sugar, preferably rock sugar; the added amount of the rock sugar is 3% to 6% of the total mass, preferably 4.75% of the total mass.

[0023] Furthermore, the bittering agent is at least one of sucrose octaacetate, bitter essence and limonin, preferably sucrose octaacetate; the added amount of the sucrose octaacetate is 0.001% to 0.004% of the total mass, preferably 0.0024% of the total mass.

[0024] The thickener is at least one of maltodextrin and soluble starch, preferably soluble starch; the added amount of the soluble starch is 0.5% to 1.5% of the total mass, preferably 1% of the total mass.

[0025] Since the color of the donkey-hide gelatin compound oral liquid is dark brown, caramel pigment is selected as the pigment; the added amount of the caramel pigment is 0.2% to 0.5% of the total mass, preferably 0.35% of the total mass.

[0026] In a preferred technical solution, in the placebo of the donkey-hide gelatin compound oral liquid, the sour agent is aged vinegar, the sweetener is at least one of xylitol, sorbitol, maltitol and rock sugar, the bittering agent is at least one of sucrose octaacetate, bitter essence and limonin, the thickener is at least one of maltodextrin and soluble starch, and the pigment is caramel pigment; preferably, the sweetener is rock sugar, the bittering agent is sucrose octaacetate, and the thickener is soluble starch.

[0027] Preferably, the donkey-hide gelatin compound oral solution placebo comprises the following components by mass percentage:

[0028] Original drug: 5% donkey-hide gelatin compound oral solution;

[0029] Flavor: 0.6% to 1.8% coffee flavor, 0.5% to 1.5% caramel flavor;

[0030] Acidulant: 1% to 3% aged vinegar;

[0031] Sweetener: 3% to 6% crystal sugar;

[0032] Bittering agent: 0.001% to 0.004% sucrose octaacetate;

[0033] Thickener: 0.5% to 1.5% soluble starch;

[0034] Pigment: 0.2% to 0.5% caramel pigment.

[0035] More preferably, the donkey-hide gelatin compound oral solution placebo comprises the following components by mass percentage:

[0036] Original drug: 5% donkey-hide gelatin compound oral solution;

[0037] Flavor: 1.2% coffee flavor, 1% caramel flavor;

[0038] Acidulant: 2% aged vinegar;

[0039] Sweetener: 4.75% crystal sugar;

[0040] Bittering agent: 0.0024% sucrose octaacetate;

[0041] Thickener: 1% soluble starch;

[0042] Color: 0.35% caramel color.

[0043] In the placebo of the donkey-hide gelatin compound oral solution described in the present application, the content can be supplemented to 100% with water.

[0044] The present invention also provides a method for preparing the above-mentioned donkey-hide gelatin compound oral liquid placebo, comprising the following steps: adding a thickener to an appropriate amount of water, heating and boiling until completely dissolved to obtain a thickener solution; placing the donkey-hide gelatin compound oral liquid original drug, flavor, acidulant, sweetener, bittering agent and pigment in a container, adding the thickener solution, adding water to make up the balance, and stirring evenly to obtain a mixed solution; and filling and sterilizing the mixed solution to obtain the donkey-hide gelatin compound oral liquid placebo.

[0045] The filling volume is 20.3-21.3 mL / vial; the placebo of donkey-hide gelatin compound oral solution is obtained by sterilization at 116-118°C for 30 minutes.

[0046] Preferably, the method for preparing the above-mentioned donkey-hide gelatin compound oral liquid placebo comprises the following steps: adding soluble starch to an appropriate amount of water and heating it until completely dissolved; placing the donkey-hide gelatin compound oral liquid original drug, coffee essence, caramel essence, aged vinegar, rock sugar, sucrose octaacetate, and caramel pigment in a container, adding the reserved soluble starch solution, adding water to make up the balance, and stirring evenly to obtain a mixed solution; filling the mixed solution with a filling volume of 20.3 to 21.3 mL per vial; and sterilizing at 116 to 118° C. for 30 minutes to obtain the donkey-hide gelatin compound oral liquid placebo.

[0047] Beneficial effects of the present invention:

[0048] Through extensive testing, screening, and optimization, the applicant selected low-dose donkey-hide gelatin compound oral liquid, coffee essence, caramel flavor, acidulant, sweetener, bittering agent, thickener, and pigment as raw materials. Preferably, low-dose donkey-hide gelatin compound oral liquid, coffee essence, caramel flavor, aged vinegar, rock sugar, sucrose octaacetate, soluble starch, and caramel pigment were selected as raw materials. A placebo was prepared by mixing the ingredients in a specific ratio. The resulting placebo was identical in appearance and color to the original donkey-hide gelatin compound oral liquid, and had a similar odor and taste, making it difficult for patients to distinguish between the two during medication.

[0049] The excipients used in the placebo of the present invention are all foods or food additives without specific activity and will not interfere with the test results. A composite flavoring with a strong layered and rich aroma is selected, and aged vinegar with a sour and mellow taste is selected as an acidulant. A certain proportion of sweeteners and bittering agents are added to the mixture. The prepared placebo has the same multi-layered properties as the original drug in terms of aroma and taste. Furthermore, its appearance and color are similar to the original drug, making it difficult for researchers and subjects to identify it. This can minimize the risk of blinding and ensure the quality of the clinical trial. DETAILED DESCRIPTION

[0050] The following describes preferred embodiments of the present invention. It should be understood that the embodiments are intended to better explain the present invention and are not intended to limit the present invention. The experimental methods used in the following examples are conventional methods unless otherwise specified; the materials and reagents used in the following examples are all commercially available unless otherwise specified.

[0051] Example 1

[0052] The placebo of the compound donkey-hide gelatin oral solution provided in this embodiment is prepared using the following raw materials in percentage by weight:

[0053] Original drug: 5% donkey-hide gelatin compound oral solution;

[0054] Flavor: 1.2% coffee flavor, 1% caramel flavor;

[0055] Acidulant: 2% aged vinegar;

[0056] Sweetener: 4.75% crystal sugar;

[0057] Bittering agent: 0.0024% sucrose octaacetate;

[0058] Thickener: 1% soluble starch;

[0059] Color: 0.35% caramel color.

[0060] The preparation method of the donkey-hide gelatin compound oral liquid placebo comprises the following steps:

[0061] (1) Preparation of coffee flavor and caramel flavor.

[0062] The preparation method of coffee essence includes the following steps: fully mixing soy protein isolate and purified water in a mass ratio of 1:3, adding protease for enzymatic hydrolysis at 60°C for 1 hour, then adjusting the temperature to 90°C for high-temperature enzyme inactivation for 10 minutes, and filtering to obtain protein hydrolyzate; preparing protein hydrolyzate, coffee bean powder, reducing sugar, and combined amino acids, and uniformly mixing them in a ratio of 20:3:20:3, wherein the reducing sugar composition and ratio are glucose:fructose = 3:2, and the combined amino acid composition and ratio are cysteine:arginine:lysine:aspartic acid = 1:2:2:1; using citric acid-sodium citrate buffer to adjust the pH of the solution to 7; heating the mixed solution at 90°C for 2 hours to carry out Maillard reaction, and filtering the reaction product through a 40-mesh sieve to obtain the essence.

[0063] The preparation method of the caramel flavor comprises the following steps: mixing propylene glycol, vanillin, vanillin propylene glycol acetal, methylcyclopentenolone and maltol in a ratio of 80:4:1:1:0.1, placing the mixture in a 50°C water bath and stirring until the mixture is completely dissolved, and then filling the mixture.

[0064] (2) Add soluble starch to an appropriate amount of water and heat until completely dissolved; take the original medicine of donkey-hide gelatin compound oral liquid, coffee essence, caramel essence, aged vinegar, rock sugar, sucrose octaacetate, and caramel color and place them in a container, add the reserved soluble starch solution, add water to make up the balance, and stir evenly to obtain a mixed solution; fill the mixed solution with a filling volume of 20.3-21.3 mL / tube; sterilize at 116-118°C for 30 minutes to obtain the donkey-hide gelatin compound oral liquid placebo.

[0065] Example 2

[0066] The placebo of the compound donkey-hide gelatin oral solution provided in this embodiment is prepared using the following raw materials in percentage by weight:

[0067] Original drug: 5% donkey-hide gelatin compound oral solution;

[0068] Flavor: 1.5% coffee flavor, 1.2% caramel flavor;

[0069] Acidulant: 2% aged vinegar;

[0070] Sweetener: 4.75% crystal sugar;

[0071] Bittering agent: 0.0024% sucrose octaacetate;

[0072] Thickener: 1% soluble starch;

[0073] Color: 0.35% caramel color.

[0074] The preparation method of the donkey-hide gelatin compound oral solution placebo is the same as that in Example 1.

[0075] Example 3

[0076] The placebo of the compound donkey-hide gelatin oral solution provided in this embodiment is prepared using the following raw materials in percentage by weight:

[0077] Original drug: 5% donkey-hide gelatin compound oral solution;

[0078] Flavor: 1.2% coffee flavor, 1% caramel flavor;

[0079] Acidulant: 1% aged vinegar;

[0080] Sweetener: 4.75% crystal sugar;

[0081] Bittering agent: 0.0024% sucrose octaacetate;

[0082] Thickener: 1% soluble starch;

[0083] Color: 0.35% caramel color.

[0084] The preparation method of the donkey-hide gelatin compound oral solution placebo is the same as that in Example 1.

[0085] Example 4

[0086] The placebo of the compound donkey-hide gelatin oral solution provided in this embodiment is prepared using the following raw materials in percentage by weight:

[0087] Original drug: 5% donkey-hide gelatin compound oral solution;

[0088] Flavor: 1.2% coffee flavor, 1% caramel flavor;

[0089] Acidulant: 2% aged vinegar;

[0090] Sweetener: 3.25% crystal sugar;

[0091] Bittering agent: 0.003% sucrose octaacetate;

[0092] Thickener: 1% soluble starch;

[0093] Color: 0.35% caramel color.

[0094] The preparation method of the donkey-hide gelatin compound oral solution placebo is the same as that in Example 1.

[0095] Example 5

[0096] The placebo of the compound donkey-hide gelatin oral solution provided in this embodiment is prepared using the following raw materials in percentage by weight:

[0097] Original drug: 5% donkey-hide gelatin compound oral solution;

[0098] Flavor: 1.2% coffee flavor, 1% caramel flavor;

[0099] Acidulant: 2% aged vinegar;

[0100] Sweetener: 4.75% crystal sugar;

[0101] Bittering agent: 0.0024% sucrose octaacetate;

[0102] Thickener: 0.5% soluble starch;

[0103] Color: 0.35% caramel color.

[0104] The preparation method of the donkey-hide gelatin compound oral solution placebo is the same as that in Example 1.

[0105] Example 6

[0106] The placebo of the compound donkey-hide gelatin oral solution provided in this embodiment is prepared using the following raw materials in percentage by weight:

[0107] Original drug: 5% donkey-hide gelatin compound oral solution;

[0108] Flavor: 1.2% coffee flavor, 1% caramel flavor;

[0109] Acidulant: 2% aged vinegar;

[0110] Sweetener: 4.75% crystal sugar;

[0111] Bittering agent: 0.0024% sucrose octaacetate;

[0112] Thickener: 1% soluble starch;

[0113] Color: 0.25% caramel color.

[0114] The preparation method of the donkey-hide gelatin compound oral solution placebo is the same as that in Example 1.

[0115] Comparative Example 1

[0116] The placebo of donkey-hide gelatin compound oral solution provided in this comparative example is made of the following raw materials in percentage by weight:

[0117] Flavor: 1.2% coffee flavor, 1% caramel flavor;

[0118] Acidulant: 2% aged vinegar;

[0119] Sweetener: 4.75% crystal sugar;

[0120] Bittering agent: 0.0024% sucrose octaacetate;

[0121] Thickener: 1% soluble starch;

[0122] Color: 0.35% caramel color.

[0123] The preparation method of the donkey-hide gelatin compound oral solution placebo is the same as that in Example 1.

[0124] Comparative Example 2

[0125] The placebo of donkey-hide gelatin compound oral solution provided in this comparative example is made of the following raw materials in percentage by weight:

[0126] Original drug: 5% donkey-hide gelatin compound oral solution;

[0127] Flavor: 2.2% coffee flavor;

[0128] Acidulant: 2% aged vinegar;

[0129] Sweetener: 4.75% crystal sugar;

[0130] Bittering agent: 0.0024% sucrose octaacetate;

[0131] Thickener: 1% soluble starch;

[0132] Color: 0.35% caramel color.

[0133] The preparation method of the donkey-hide gelatin compound oral solution placebo is the same as that in Example 1.

[0134] Comparative Example 3

[0135] The placebo of donkey-hide gelatin compound oral solution provided in this comparative example is made of the following raw materials in percentage by weight:

[0136] Original drug: 5% donkey-hide gelatin compound oral solution;

[0137] Flavor: 2.2% caramel flavor;

[0138] Acidulant: 2% aged vinegar;

[0139] Sweetener: 4.75% crystal sugar;

[0140] Bittering agent: 0.0024% sucrose octaacetate;

[0141] Thickener: 1% soluble starch;

[0142] Color: 0.35% caramel color.

[0143] The preparation method of the donkey-hide gelatin compound oral solution placebo is the same as that in Example 1.

[0144] Comparative Example 4

[0145] The placebo of donkey-hide gelatin compound oral solution provided in this comparative example is made of the following raw materials in percentage by weight:

[0146] Original drug: 5% donkey-hide gelatin compound oral solution;

[0147] Flavor: 2.5% coffee flavor, 2% caramel flavor;

[0148] Acidulant: 2% aged vinegar;

[0149] Thickener: 1% soluble starch;

[0150] Color: 0.35% caramel color.

[0151] The preparation method of the donkey-hide gelatin compound oral solution placebo is the same as that in Example 1.

[0152] Comparative Example 5

[0153] The placebo of donkey-hide gelatin compound oral solution provided in this comparative example is made of the following raw materials in percentage by weight:

[0154] Original drug: 5% donkey-hide gelatin compound oral solution;

[0155] Flavor: 1.2% coffee flavor, 1% caramel flavor;

[0156] Acidulant: 0.1% glacial acetic acid;

[0157] Sweetener: 4.75% crystal sugar;

[0158] Bittering agent: 0.0024% sucrose octaacetate;

[0159] Thickener: 1% soluble starch;

[0160] Color: 0.35% caramel color.

[0161] The preparation method of the donkey-hide gelatin compound oral solution placebo is the same as that in Example 1.

[0162] Comparative Example 6

[0163] The placebo of donkey-hide gelatin compound oral solution provided in this comparative example is made of the following raw materials in percentage by weight:

[0164] Original drug: 5% donkey-hide gelatin compound oral solution;

[0165] Flavor: 1.2% coffee flavor, 1% caramel flavor;

[0166] Acidulant: 2% aged vinegar;

[0167] Sweetener: 4.75% crystal sugar;

[0168] Bittering agent: 0.0024% sucrose octaacetate;

[0169] Thickener: 0.3% soluble starch;

[0170] Color: 0.35% caramel color.

[0171] The preparation method of the donkey-hide gelatin compound oral solution placebo is the same as that in Example 1.

[0172] Test example:

[0173] In order to clarify the similarity between the placebo of the compound donkey-hide gelatin oral solution of the present invention and the original drug, the following experiments were conducted.

[0174] Manual evaluation method: Using the manual scoring method, 10 evaluators were randomly selected to evaluate the donkey-hide gelatin compound oral liquid placebo prepared in the examples and comparative examples from four aspects: appearance, color, smell, and taste. The donkey-hide gelatin compound oral liquid was used as the control sample. The evaluators scored by looking, tasting, and smelling, and followed the principle of independent scoring and non-interference when scoring. The score distribution range is 0 to 10 points. The higher the score, the higher the similarity. 10 points represents complete consistency with the sample, and 0 points represents complete inconsistency. The evaluators scored according to the actual situation and calculated the average score of the four items (wherein: appearance and color ≥7 points are qualified, and smell and taste ≥6 points are qualified).

[0175] The test results were analyzed and processed using Excel software and expressed as “mean ± standard deviation”. The t-test method was used with a test level of α = 0.05.

[0176] The test results are shown in Table 1.

[0177] Table 1 Placebo score results

[0178]

[0179]

[0180] As shown in the above test results, the donkey-hide gelatin compound oral liquid placebo prepared in Example 1 is consistent with the appearance and color of the donkey-hide gelatin compound oral liquid, and the smell and mouthfeel are similar, and there is no statistical significance between the two (P>0.05), indicating that the similarity between the donkey-hide gelatin compound oral liquid placebo provided by the present invention and the original medicine of the donkey-hide gelatin compound oral liquid is higher and can be used for clinical trials. The overall score of Comparative Example 1 is not significantly different from that of Example 1, indicating that when the original medicine is not added, the placebo prepared using only essence and flavoring agents can obtain a high similarity to the original medicine. It can be seen from Example 1 and Comparative Examples 2, 3, 4, and 5 that the placebo prepared using a single essence does not have a hierarchy in smell and mouthfeel, and in the absence of sweeteners and bittering agents, simply increasing the concentration of essence can not better simulate the mouthfeel of Chinese medicinal materials. It can also be seen that selecting aged vinegar as an acidity regulator effectively avoids the abruptness of the single acidulant mouthfeel and increases the richness of the placebo mouthfeel. Comparing the results of Example 1 and Comparative Example 6, it can be seen that when the content of soluble starch is 1%, the appearance and taste of the prepared donkey-hide gelatin compound oral liquid placebo are similar to those of the original donkey-hide gelatin compound oral liquid.

[0181] In summary, the present invention provides a placebo of donkey-hide gelatin compound oral liquid comprising a low-dose donkey-hide gelatin compound oral liquid, coffee essence, caramel essence, acidulant, sweetener, bittering agent, thickener and pigment. The obtained placebo is consistent with the original donkey-hide gelatin compound oral liquid in appearance and color, and similar in smell and taste. It is difficult for patients to distinguish them when taking the medicine, which is of great significance to the development of clinical trials of donkey-hide gelatin compound oral liquid.

[0182] The above is only a preferred embodiment of the present application. It should be pointed out that for ordinary technicians in this technical field, several improvements and updates can be made without departing from the principles of the present application. These improvements and updates should also be regarded as the scope of protection of the present application.

Claims

1. A placebo of donkey-hide gelatin compound oral solution, characterized in that: The invention comprises the raw material of donkey-hide gelatin compound oral liquid, flavor, acidulant, sweetener, bittering agent, thickener and pigment, and optional water; the flavor comprises coffee flavor and caramel flavor.

2. The placebo according to claim 1, characterized in that The invention comprises 2-10% of the original medicine of the compound donkey-hide gelatin oral liquid, and preferably comprises 5% of the original medicine of the compound donkey-hide gelatin oral liquid.

3. The placebo according to claim 1 or 2, characterized in that The sour agent is aged vinegar, the sweetener is at least one of xylitol, sorbitol, maltitol and rock sugar, the bittering agent is at least one of sucrose octaacetate, bitters and limonin, the thickener is at least one of maltodextrin and soluble starch, and the pigment is caramel pigment; preferably, the sweetener is rock sugar, the bittering agent is sucrose octaacetate, and the thickener is soluble starch.

4. The placebo according to claim 3, characterized in that Calculated by mass percentage, it includes the following components: Original drug: 5% donkey-hide gelatin compound oral solution; Flavor: 0.6% to 1.8% coffee flavor, 0.5% to 1.5% caramel flavor; Acidulant: 1% to 3% aged vinegar; Sweetener: 3% to 6% crystal sugar; Bittering agent: 0.001% to 0.004% sucrose octaacetate; Thickener: 0.5% to 1.5% soluble starch; Pigment: 0.2% to 0.5% caramel pigment.

5. The placebo according to claim 4, characterized in that Calculated by mass percentage, it includes the following components: Original drug: 5% donkey-hide gelatin compound oral solution; Flavor: 1.2% coffee flavor, 1% caramel flavor; Acidulant: 2% aged vinegar; Sweetener: 4.75% crystal sugar; Bittering agent: 0.0024% sucrose octaacetate; Thickener: 1% soluble starch; Color: 0.35% caramel color.

6. The placebo according to any one of claims 1-2, 4-5, characterized in that The method for preparing coffee essence comprises the following steps: fully mixing soy protein isolate with water, adding protease for enzymatic hydrolysis, then inactivating the enzyme, and filtering to obtain a protein hydrolyzate; preparing the protein hydrolyzate, coffee bean powder, reducing sugar, and combined amino acids, and mixing them uniformly; adjusting the pH of the solution to 7; subjecting the mixed solution to a Maillard reaction, and sieving the reaction product to obtain the coffee essence; The preparation method of the caramel flavor comprises the following steps: mixing propylene glycol, vanillin, vanillin propylene glycol acetal, methylcyclopentenolone and maltol, and heating and stirring until the mixture is completely dissolved.

7. The placebo according to claim 6, characterized in that The preparation method of the coffee essence comprises the following steps: fully mixing soy protein isolate and water in a mass ratio of 1:1-5, adding protease and performing enzymatic hydrolysis at 50-70°C for 0.5-3 hours, then adjusting the temperature to 80-100°C to inactivate the enzyme for 5-20 minutes, and filtering to obtain a protein hydrolyzate; preparing the protein hydrolyzate, coffee bean powder, reducing sugar, and combined amino acids, and uniformly mixing them in a ratio of (15-25):3:(15-20):3, wherein the composition and ratio of the reducing sugar are glucose:fructose=1-5:2, and the composition and ratio of the combined amino acids are cysteine:arginine:lysine:aspartic acid=1:(1-2):(1-2):1; and adjusting the pH of the solution to 7 using a buffer solution; The mixed solution is heated at 80-100°C for 1-3 hours to carry out the Maillard reaction, and the reaction product is passed through a 20-60 mesh sieve to obtain the product; The preparation method of the caramel flavor comprises the following steps: mixing propylene glycol, vanillin, vanillin propylene glycol acetal, methylcyclopentenolone, and maltol in a mass ratio of (40-120): (2-8): (0.5-2): (0.5-2): 0.1, and heating and stirring at 40-60° C. until the mixture is completely dissolved.

8. The placebo according to claim 7, characterized in that The preparation method of the coffee essence comprises the following steps: fully mixing soy protein isolate and purified water in a mass ratio of 1:3, adding protease to perform enzymatic hydrolysis at 60°C for 1 hour, then adjusting the temperature to 90°C to inactivate the enzyme for 10 minutes, and filtering to obtain a protein hydrolyzate; preparing the protein hydrolyzate, coffee bean powder, reducing sugar, and combined amino acids, and uniformly mixing them in a ratio of 20:3:20:3, wherein the composition and ratio of the reducing sugar are glucose:fructose=3:2, and the composition and ratio of the combined amino acids are cysteine:arginine:lysine:aspartic acid=1:2:2:1; The pH of the solution was adjusted to 7 using a citric acid-sodium citrate buffer solution; the mixed solution was heated at 90° C. for 2 h to perform a Maillard reaction, and the reaction product was passed through a 40-mesh sieve; The preparation method of the caramel flavor comprises the following steps: mixing propylene glycol, vanillin, vanillin propylene glycol acetal, methylcyclopentenolone, and maltol in a mass ratio of 80:4:1:1:0.1, and heating and stirring at 50° C. until the mixture is completely dissolved.

9. A method for preparing the placebo of the donkey-hide gelatin compound oral solution according to any one of claims 1 to 8, characterized in that: The following steps are involved: Add a suitable amount of thickener to water and heat until completely dissolved to obtain a thickener solution; place the original drug of donkey-hide gelatin compound oral solution, flavor, acidulant, sweetener, bittering agent and pigment in a container, add the thickener solution, add water to make up the balance, and stir evenly to obtain a mixed solution; The mixed solution was filled and sterilized to obtain a placebo of donkey-hide gelatin compound oral solution.

10. The method according to claim 9, characterized in that The filling volume is 20.3-21.3 mL / vial; the placebo of donkey-hide gelatin compound oral solution is obtained by sterilization at 116-118°C for 30 minutes.

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