Iron-skin dendrobium chewable tablet

Abstract

To provide a chewable tablet containing iron-skin dendrobium, Polygonati Rhizoma, and Ziziphus jujuba which has excellent external appearance, mouthfeel, hardness, weight difference and the like.SOLUTION: A chewable tablet contains Iron-skin Dendrobium, Polygonati Rhizoma and Ziziphus jujuba in a weight ratio of (4-8.5):(1-4):(0.5-4), and furthermore, contains sweetener, flavor agent, filler and flow aid.SELECTED DRAWING: Figure 22

Description

[Technical Field]

[0001] The present invention relates to the pharmaceutical field, and particularly to the recipe composition of Dendrobium iron oxide chewable tablets. [Background technology]

[0002] Tablets are solid preparations made through a specific process by homogenously mixing active ingredients and additives and then blending them in a specific proportion. Tablets are mainly composed of coated tablets, chewable tablets, and effervescent tablets. Chewable tablets are processed into granules in the mouth, so they can be eaten without water and are easy to swallow. They are recognized as the most easily edible dosage form. Because chewable tablets are processed in the mouth, they have the advantages of rapid absorption and high bioavailability, making them particularly useful for the elderly, children, and those with intestinal problems. However, because chewable tablets are processed in the mouth, there are high requirements for mouthfeel and taste, so additives have a significant impact on the quality of the finished chewable tablet.

[0003] Direct powder compression is the process of grinding drug substances and excipients, mixing them uniformly in a specific ratio, and then compressing them into tablets. This method is characterized by its simple process, simple procedure, and convenient operation. Because both the drug substances and excipients in powder compression are in powder form and there is no physical adhesion process, powder compression places strict requirements on the compressed powder. If the materials are loose or have poor flow properties, the finished product may suffer from cracking, broken tops, uneven tablet weight, and non-uniform active ingredients. While raw materials generally require excellent flowability and compressibility, most traditional Chinese medicine ingredients do not meet the requirements for direct compression. Many researchers have attempted to achieve direct compression standards by using methods such as spray drying and ultrafine grinding to process the powder. The direct powder compression process for making chewable tablets using traditional Chinese medicine ingredients is relatively simple, but the requirements for additives are very strict, and common traditional Chinese medicine ingredients are difficult to compress due to their relatively strong fibrous nature. Therefore, in order to improve the efficiency and quality of tableting and reduce the probability of problems, selecting additives that can be used to make tablets using direct powder compression is an important part of recipe design. The additives used in direct compression must mainly have the characteristics of good fluidity, good compressibility, small particle size difference between the additives and raw materials, and low hygroscopicity.

[0004] Chewable tablets are chewed into small particles in the mouth and swallowed, so there is no disintegration process and no need to add disintegrants. Because traditional Chinese medicine ingredients themselves have an unpleasant smell or texture, chewable tablets must have a pleasant texture to match the characteristics of chewing and swallowing in the mouth. Furthermore, chewable tablets have strict requirements for the fluidity and moldability of the powder or particles before tableting, so flavoring agents must improve the mouthfeel of chewable tablets while also having characteristics such as excellent thermal stability, fluidity, and low moisture absorption. Therefore, the selection of flavoring agents is very important in the research, development, and production of chewable tablets.

[0005] Additives, generally inactive ingredients, play an important role in the design and development of pharmaceutical formulations. Selecting the appropriate type and proportion of additives not only affects the solubility, stability, and absorbability of the matrix and the physical properties of the tablet, but also improves the rheological properties of the tablet, its compactibility, and mechanical strength, thereby enhancing its stability and pharmacodynamic properties. Additives increase the volume and weight of the formulation, providing the necessary processability and protecting the properties of the raw materials to a certain extent. They also contribute to the proportion of active ingredients, reducing costs and improving the palatability for consumers. Commonly used fillers include starches, sugars, celluloses, and inorganic salts. Powder flowability not only affects the normal production process of pharmaceutical formulations, but also the quality of the formulation. For example, powders are prone to blockage or uneven filling during filling and tableting, resulting in unstable tablet quality and even tablet fractures or porosity. Therefore, the fluidity of the powder must be considered and improved during tablet production. Therefore, it is necessary to predict the flowability of the powder raw material from the hopper, the difficulty of packaging and separate packaging, weight variation, and content uniformity.

[0006] The present invention provides chewable tablets with excellent comprehensive indices such as appearance, mouthfeel, hardness, and weight difference through the selection of additives and the design of the recipe. Summary of the Invention [Problem to be solved by the invention]

[0007] The present invention aims to provide chewable tablets made from Dendrobium sieboldii in order to solve the problems existing in the prior art. The present invention solves the problems of poor compactibility, rough surface, and poor mouthfeel of chewable tablets made by direct compression through the optimization of additives. The chewable tablets made by direct compression using the recipe of the present invention have excellent overall indices such as appearance, mouthfeel, hardness, and weight difference. [Means for solving the problem]

[0008] Dendrobium chinense chewable tablets are prepared by blending Dendrobium chinense, Phellodendron bark, and Jujube in a mass ratio of (4-8.5):(1-4):(0.5-4).

[0009] The Dendrobium iron oxide chewable tablets further contain a sweetener, a flavoring agent, a filler, and a flow aid, wherein the sweetener is one or a combination of erythritol, mannitol, trichlorosucrose, or xylitol, the flavoring agent is one or a combination of whey protein, peppermint essence, or oyster-derived peptide, the filler is microcrystalline cellulose, and the flow aid is magnesium stearate.

[0010] The sweetener of the Dendrobium iron oxide chewable tablets is a composition of erythritol, mannitol and trichlorosucrose.

[0011] The mass fractions of the Dendrobium chinense chewable tablets recipe are Dendrobium chinense 20%-42.50%, Phellodendron amurense 5.00%-20%, Jujube 2.50%-20.00%, Erythritol 5.00-25.00%, Mannitol 5.00-25.00%, Whey protein 5.00-7.50%, Oyster peptide 1.00-4.00%, Peppermint essence 0.50-2.50%, Citric acid 0.50-1.00%, Trichlorosucrose 0.05-0.25%, Magnesium stearate 0.05-1.00%, Microcrystalline cellulose 7.50-15.00%. [Effects of the Invention]

[0012] Through the creation of a regression equation and target optimization analysis, the present invention obtains the following ratio of drug substance addition: Dendrobium chinense: Huangjiang: Jujube = (4-8.5): (1-4): (0.5-4). The final experimental results showed that the content of active ingredients detected in this recipe was high. This indicates that the combined recipe of Dendrobium chinense, Huangjiang, and Jujube can achieve synergistic effects on active ingredients. The polysaccharide content in this proportional Chinese medicine recipe was 159.64 mg / g, the flavonoid content was 79.44 mg / g, and the polyphenol content was 78.10 mg / g.

[0013] By optimizing additives, the present invention has solved the problems of poor moldability, rough surfaces, and poor mouthfeel when making chewable tablets using direct compression, and has unexpectedly discovered that using a combination recipe of erythritol + trichlorosucrose + mannitol as a sweetener can achieve a synergistic effect in terms of the moldability and mouthfeel of chewable tablets.The chewable tablets made using the recipe of the present invention using direct compression have excellent comprehensive indicators such as appearance, mouthfeel, hardness, and weight difference. [Brief explanation of the drawings]

[0014] [Figure 1] FIG. 1 is a diagram showing the optimization of extraction conditions for detecting polysaccharide content using the "phenol-sulfuric acid method" of the present invention. [Figure 2] FIG. 1 is a diagram showing the optimization of reaction conditions for detecting polysaccharide content using the "phenol-sulfuric acid method" of the present invention. [Figure 3] 1 is a standard graph of glucose (0.09 mg / mL) according to the present invention. [Figure 4] FIG. 1 is a diagram comparing the reaction between the standard solution of the present invention and hot water. [Figure 5] FIG. 2 is a comparison diagram of the degree of extraction between methanol and ethanol according to the present invention. [Figure 6] 1 is a standard graph of rutin (0.2 mg / mL) of the present invention. [Figure 7] 1 shows the optimized reaction conditions for measuring polyphenol content using the "Folin phenol method" of the present invention ((a) relationship between total polyphenol content and reflux time, (b) relationship between total polyphenol content and reaction time). [Figure 8] 1 shows an optimization diagram of the reaction solution volume for measuring polyphenol content using the "Folin phenol method" of the present invention ((a) relationship between total polyphenol content and Folin phenol, (b) relationship between total polyphenol and sodium carbonate). [Figure 9] 1 is a standard graph of gallic acid (0.1 mg / mL) of the present invention. [Figure 10] Contour plot (left) and 3D effect surface diagram showing the effect of three substrates of the present invention on polysaccharide mass fraction. [Figure 11] Contour plot (left) and 3D effect surface (right) of the effect of three substrates of the present invention on flavonoid mass fraction. [Figure 12] Contour plot (left) and 3D effect surface (right) of the effect of three substrates of the present invention on polyphenol mass fraction. [Figure 13] 1 is a schematic diagram of angle of repose measurement according to the present invention. [Figure 14] Finished chewable tablets prepared with different sweetener blends of the present invention. [Figure 15] The finished chewable tablets were prepared using different positive control recipes of the present invention ((a) substrate only: Dendrobium:Jujube:Yellow Jelly = 4:4:2, (b) substrate only: Dendrobium:Jujube:Yellow Jelly = 7:2:1, (c) substrate only: Dendrobium:Jujube:Yellow Jelly = 85:5:10, (d) additives only, no substrate). [Figure 16] The influence of erythritol mass fraction of the present invention on the quality of Dendrite chewable tablets. [Figure 17] The influence of mannitol mass fraction of the present invention on the quality of Dendrite chewable tablets. [Figure 18] The effect of whey protein mass fraction of the present invention on the quality of Dendrite chewable tablets. [Figure 19] FIG. 1 is a 3D response surface diagram of the effect of erythritol and mannitol mass fractions on overall scoring according to the present invention. [Figure 20] FIG. 1 is a 3D response surface diagram of the effect of erythritol and whey protein mass fraction of the present invention on overall score. [Figure 21] FIG. 1 is a 3D response surface diagram of the effect of mannitol and whey protein mass fraction of the present invention on overall score. [Figure 22] The chewable tablets of the present invention are prepared with different ratios of substrate and additives. DETAILED DESCRIPTION OF THE INVENTION

[0015] The present invention will be described in detail below in conjunction with the drawings and specific embodiments.

[0016] 1. Experiment 1: Determining the ingredient ratio of Dendrobium chinense chewable tablets 1.1 Experimental materials and equipment <Experimental materials> Dendrobium iron oxide - Leqing Dagongshan Dendrobium Co., Ltd., dried rhizome of Huangjing - Bozhou Linge Pharmaceutical Co., Ltd., fresh jujube - Haosuang▲Yi'er▼ Health Food Co., Ltd., glucose standard, gallic acid standard, rutin standard - Hefei Boye Biotechnology Co., Ltd., phenol, concentrated sulfuric acid, purified water, absolute ethanol, sodium carbonate, Folin phenol, sodium hydroxide, sodium nitrite, aluminum nitrate - Shanghai McGraw-Hill Biochemical Technology Co., Ltd. All reagents used in the experiments are of analytical grade.

[0017] <Experimental equipment> DHG-9076A-Electric heating constant temperature air drying oven-Shanghai Jinghong Experimental Equipment Co., Ltd., HBM-109-Ultrafine particle grinder-Rui'an Hanbo Mechanical Electric Co., Ltd., ZNCL-T - Electric heating jacket - Shanghai Hongyi Instrument Equipment Co., Ltd., TG16G - Centrifuge - Hunan Kaida Scientific Instruments Co., Ltd., IMS - 70 - Ice machine - Changshu Xueke Electrical Equipment Co., Ltd., HH ―420―Digital display constant temperature water tank―Hoenxi Yitech (Shanghai) Co., Ltd., BSA224S―CW―Electronic analytical balance―Germany Sartorius, UV―5200―Visible light spectrophotometer―Shanghai Yuan Analytical Instrument Co., Ltd., R-210―Rotary evaporator―Switzerland―BUCHI, KQ―250B―Ultrasonic cleaning machine―Kunshan Ultrasonic Instrument Co., Ltd.

[0018] 1.2 Experimental Method <Preparation of complex compound pharmaceutical raw materials> After washing and removing impurities, Dendrobium chinense, Xanthomonas orientalis and Jujube, they are cut into small pieces, removed the moisture, and dried in hot air at 100-120°C. After drying, the pharmaceutical raw materials are crushed in an ultra-fine particle grinder and passed through a 100-mesh sieve to obtain fine powder with a particle size of 20-30 μm. These are then placed in valve bags and stored away from direct light for future use.

[0019] Preparation of complex compounded pharmaceutical ingredients Erythritol was used as the sweetener in the preliminary experiment. The Dendrobium sieve, Yellow Jing, and jujube were then sieved, mixed uniformly, and compressed to obtain tablets, which were then subjected to sensory evaluation. Finally, based on the premise that the mass ratio of the drug substance and excipients was 1:1, the mass fraction data ranges of the substrates were determined: Dendrobium sieve 40-85%, Yellow Jing 10-40%, and jujube 5-40%, respectively. The D-optimal mixture (DOE) experimental design in Design-Expert11 software was used to optimize the composite blend ratio of the substrates, and a three-factor, two-level mixture design test was conducted. The design factors and levels are shown in Table 1. Different mass fractions of Dendrobium sieve, Yellow Jing, and jujube were used as independent variables, and the mass fractions of polysaccharides, flavonoids, and polyphenols measured in the blend system were used as evaluation indicators to examine the effects of the independent variables on the evaluation indicators. The specific compounded pharmaceutical raw material addition ratios are shown in Table 2. According to the amount of drug substance added provided in the table, the drug substance is precisely weighed, and a total of 16 samples are taken for measurement.

[0020] [Table 1]

[0021] [Table 2]

[0022] 1.3 Measurement method for polysaccharide content in complex pharmaceutical raw materials <Preparation of sample solution> Accurately weigh 1 g of the mixed pharmaceutical ingredients and place it in a 250 mL three-neck flask. Add 200 mL of purified water and cool to room temperature. Dissolve in a 250 mL bottle and filter. Transfer 2 mL of the filtrate to a 15 mL tube, add 8 mL of absolute ethanol, shake evenly, and refrigerate for 2 hours. Remove from the tube, centrifuge (6000 rpm, 10 min), remove the supernatant, and wash twice with 80% ethanol for precipitation, removing 8 mL of supernatant each time. Dissolve the precipitate in hot water, transfer to a 25 mL volumetric flask, cool, adjust to the graduated line, and shake evenly to obtain the sample solution.

[0023] <Preparation of control solution> Accurately weigh out 0.009 g of anhydrous glucose standard and dissolve it in a 100 mL volumetric flask. Add purified water up to the graduation line. Prepare a control solution containing 90 μg (i.e., 0.09 mg / mL) per mL and prepare it for use. Measure the absorbance (wp) at a wavelength of maximum absorption of 500 nm [8].

[0024] <Optimization of analytical conditions> (1) Extraction time: Accurately weigh four equal portions of the mixed pharmaceutical raw material powder, heat and extract for 1 hour, 1.5 hours, 2 hours, and 2.5 hours, respectively, and then extract the remaining material. The remaining procedures are as in 2.2.3.1, adding an appropriate amount of sulfuric acid solution and 5% phenol solution, and measuring the absorbance value (A) at the maximum wavelength. All other experimental conditions are set to intermediate values.

[0025] (2) Alcohol precipitation time: Accurately measure 4 portions of the test material solution, add anhydrous ethanol, and then refrigerate them in the refrigerator for 1 hour, 1.5 hours, 2 hours, and 2.5 hours, and then remove them. The other operations are as in 2.2.3.1, and the absorbance value (A) is measured at the maximum wavelength. All other experimental conditions are conducted at intermediate values.

[0026] (3) Sulfuric acid dosage: Prepare four portions of the sample solution using the method in 2.2.3.1. Add 5 mL, 10 mL, 15 mL, or 20 mL of sulfuric acid and an appropriate amount of 5% phenol to each sample solution. Measure the absorbance value (A) at the maximum wavelength. Use intermediate values ​​for all other experimental conditions.

[0027] (4) Phenol dosage: Prepare four aliquots of sample solution using the method in 2.2.3.1. Add 1 mL, 2 mL, 3 mL, 4 mL, and 5 mL of 5% phenol and an appropriate amount of concentrated sulfuric acid to the sample solution, respectively, and measure the absorbance value (A) at the maximum wavelength. All other experimental conditions should be set to intermediate values.

[0028] <Creating a standard graph> Accurately measure 0 mL, 0.6 mL, 1.2 mL, 1.8 mL, 2.4 mL, and 3.0 mL of glucose control solution, place each in a 25 mL stoppered test tube, add water until the total volume is 3 mL, add 5% phenol solution, shake evenly, add 15 mL of sulfuric acid solution, place in a boiling water bath for 20 minutes, remove and immediately place in an ice water bath for 5 minutes, remove and leave for 10 minutes before measuring.

[0029] <Content measurement> Transfer 1 mL of the sample solution, develop color using the above method, and create a standard graph using glucose standard solutions of different concentrations. Determine the mass fraction of polysaccharides in the compounded pharmaceutical raw materials based on the standard graph and dilution factor. The calculation formula is (2-1):

[0030]

number

[0031] 1.4 Determination method for flavonoid content in mixed pharmaceutical raw materials <Preparation of sample solution> Accurately weigh 1g of crude powder of different proportions of pharmaceutical ingredients, add 50mL of absolute alcohol, ultrasonicate for 30 minutes, then cool to room temperature. Collect the filtrate, shred the filter paper, and place it in a beaker flask together with the filter cake. Add 50mL of 80% alcohol, ultrasonicate for 45 minutes, cool to room temperature, extract the filtrate, and combine the two filtrates. Concentrate the filtrate under reduced pressure and steam dry, then add 10mL of 80% ethanol to redissolve. Centrifuge the redissolved solution (6000rpm, 10min) to remove insoluble impurities, then transfer to a 10mL volumetric flask, adjust to the graduated line, and shake evenly to obtain the sample solution.

[0032] <Preparation of control solution> Accurately weigh 10 mg of rutin standard and place it in a 50 mL brown volumetric flask. Add 80% ethanol solution to the scale line to prepare a 0.2 mg / mL solution for use. Measure the absorbance at the maximum absorption wavelength of 505 nm.

[83] .

[0033] <Optimization of reaction conditions> (1) Optimization of extraction conditions for test samples: 1g of each of the three portions of mixed pharmaceutical ingredients was weighed out accurately, and 50mL of 80% ethanol was added to each portion. Mix uniformly, reflux for 30 minutes, and then the volume was adjusted to 50mL with 80% ethanol. Cool to room temperature, and the filtrate was collected. The filter paper was shredded and placed in a three-neck flask with the filter cake. 50mL of 80% ethanol was added, refluxed for 45 minutes, and cooled to room temperature. The filtrate was extracted, and the two filtrates were combined. The filtrate was concentrated under reduced pressure and steamed to dryness, and 10mL of 80% ethanol was added to redissolve the solution. The redissolved solution was centrifuged (6000rpm, 10min) to remove insoluble impurities. The solution was transferred to a 10mL volumetric flask, adjusted to the measuring line, and shaken to obtain the test sample. Of the other two portions of the mixed drug, one portion was added with 50 mL of absolute alcohol and ultrasonicated for 30 minutes, and the other portion was added with 50 mL of methanol and ultrasonicated for 30 minutes. After removing the solution, ultrasonicated it twice as described above to extract the filtrate, which was then concentrated under reduced pressure and redissolved to obtain the test product solution. The test product solution was reacted under the reaction conditions at the above detection wavelength. The absorbance value (A) was measured at the maximum absorption wavelength.

[0034] (2) Optimization of the extraction time of the test products: The total time of hot water extraction, ethanol ultrasonic extraction, and methanol ultrasonic extraction was set to 15, 30, 45, 60, 75, 90, and 105 minutes, and the absorbance value (A) was measured at the maximum absorption wavelength.

[0035] <Creating a standard graph> Accurately measure 1.5mL, 2mL, 2.5mL, 3mL, 3.5mL, and 4mL of rutin control solution and place them in 25mL stoppered test tubes, add 80% absolute ethanol up to 5mL, add 1mL of 5% sodium nitrite solution to each, shake evenly, react for 6 minutes, add 1mL of 10% aluminum nitrate solution, react for 6 minutes, add 4% sodium hydroxide, shake evenly, wait for 15 minutes of reaction time, and then measure.

[0036] <Measurement of content> Transfer 1 mL of the sample solution and develop color using method 2.2.4.3. Create a standard graph using rutin standard solutions of different concentrations. Determine the mass fraction of flavonoids in the compounded pharmaceutical raw materials using the standard graph and dilution factor, and use the calculation formula (2-1).

[0037] 1.4 Measurement method for polyphenols in mixed pharmaceutical raw materials <Preparation of sample solution> Accurately weigh 1 g of crude pharmaceutical powder in different proportions, add 50 mL of 60% absolute alcohol, reflux at 80°C for 1.5 hours, cool, and filter through a Buchner funnel. Transfer the filtrate into a 50 mL brown volumetric flask and make up to the measuring line with 60% absolute alcohol to obtain the sample solution.

[0038] <Preparation of control solution> Accurately weigh 10 mg of gallic acid standard into a 100 mL brown volumetric flask, add 60% ethanol solution to the scale line, and prepare a 0.1 mg / mL solution for use. Measure the absorbance at a maximum wavelength of 778 nm.

[0039] <Optimization of analytical conditions> (1) Reflux time: Accurately weigh 4 portions of the same proportion of crude pharmaceutical powder, fix the volume fraction of ethanol, extract the temperature, reflux the test material for 1 hour, 1.5 hours, 2 hours, and 2.5 hours, and then measure the absorbance value (A) at the maximum wavelength.

[0040] (2) Reaction temperature: Accurately weigh 4 portions of the test material, and add the appropriate amount of Folin phenol solution and 10% sodium carbonate solution to each. Fix the reaction time (intermediate value), and react the solution to be measured at 40℃, 45℃, 50℃, and 55℃ for 0.5 hours, avoiding direct light, and measure the absorbance value (A) at the maximum absorption wavelength. The other procedures are the same as above.

[0041] (3) Folinphenol dosage: Accurately measure 5 portions of the test solution, add 1 mL, 2 mL, 3 mL, 4 mL, and 5 mL of folinphenol, fix the amount of 10% sodium carbonate added (intermediate value), and measure the absorbance value (A) at the maximum absorption wavelength.

[0042] (4) Sodium carbonate dosage: Accurately measure 5 portions of the test solution, add 7 mL, 8 mL, 9 mL, and 10 mL of 10% sodium carbonate solution, fix the amount of folin phenol added (intermediate value), and measure the absorbance value (A) at the maximum absorption wavelength.

[0043] <Creating a standard graph> Accurately measure 0.1mL, 0.2mL, 0.3mL, 0.4mL, 0.5mL, and 0.6mL of the gallic acid control solution, place each in a 25mL stoppered test tube, add 60% absolute ethanol up to 1mL, add 3mL of folin phenol, shake evenly, leave to stand for 5 minutes, add 8mL of 10% sodium carbonate solution, add water to make up to 25mL, react at 50℃ for 0.5 hours away from direct sunlight, remove from the heat, cool to room temperature, and measure.

[0044] <Measurement of content> Transfer 1 mL of the sample solution and develop color using method 2.2.5.3. Create a standard graph using gallic acid standard solutions of different concentrations. Determine the mass fraction of polyphenols in the compounded pharmaceutical raw materials using the standard graph and dilution factor, and use the calculation formula (2-1).

[0045] <Data processing> All experiments were performed by repeating the measurements three times, starting from sample preparation, and taking the average of the three measurements as the measurement results. The final results were analyzed by Excel, plotted using Origin2021 software, and subjected to fitting, analysis of variance, and significance analysis using two polynomial regressions on the data using Design-Expert11 software.

[0046] 1.5 Results and Analysis <Content of mixed pharmaceutical raw material polysaccharides> <Determining analytical conditions> Figure 1 shows the optimized extraction conditions for detecting polysaccharide content using the phenol-sulfuric acid method. As can be seen, as the extraction time increases, the polysaccharide content initially increases significantly and then decreases. This is due to insufficient extraction time, but if the extraction time is too long, the polysaccharide content tends to decrease, which may be due to polysaccharide decomposition. Therefore, the optimal extraction time for polysaccharide content is 2 hours using boiling water. The extract is then added with absolute ethanol and refrigerated in a refrigerator. The purpose is to allow the active substances in the extract to precipitate in the absolute ethanol environment. This process is called the "alcohol precipitation process." As can be seen from the "alcohol precipitation process," the precipitation of polysaccharides increases with increasing refrigeration time. The precipitation of polysaccharides is greatest after refrigeration for 2 hours. Therefore, in this experiment, the optimal extraction method for polysaccharide content was to extract in boiling water for 2 hours, then take 2 mL of the filtrate and put it into a 15 mL centrifuge tube, add 8 mL of absolute ethanol, and shake evenly to obtain the polysaccharide content.

[0047] Figure 2 shows the optimized reaction conditions for detecting polysaccharide content using the phenol-sulfuric acid method. As can be seen, as the amount of sulfuric acid increases, the measured polysaccharide content first increases significantly and then begins to decrease. The reason for the increase is that, when sulfuric acid is used as the reaction solution, adding 5mL or 10mL of sulfuric acid does not allow the polysaccharides to fully react in the system. Therefore, as the amount of sulfuric acid added to the reaction solution increases, the polysaccharides in the system are fully reacted, increasing the polysaccharide content. Subsequently, as the amount of sulfuric acid added to the reaction solution increases, the polysaccharide content in the system begins to decrease. This is because when 15mL of sulfuric acid is added to the reaction solution, the polysaccharides in the system are fully reacted. Adding more reaction solution does not increase the polysaccharide content; instead, the volume of the solution in the system increases, decreasing the concentration of the polysaccharide content, resulting in a downward trend. By the same logic, when the amount of phenol in (b) is 3mL, the polysaccharides in the system are fully reacted, and then the volume of the solution increases, causing the polysaccharide content to decrease. In summary, the optimal reaction conditions for polysaccharide content are when 15 mL of sulfuric acid and 3 mL of 5% phenol solution are added to the sample solution or standard solution, resulting in a peak in the profile and a maximum measured polysaccharide content.

[0048] <Creating a standard graph> The experiment was carried out as above, and the corresponding reagent was used as a blank reference, and the color was developed in the same manner. The absorption peak value A was detected at 500 nm, and the mass concentration was taken as the abscissa and the absorbance as the ordinate, and the linear equation y = 10.795x + 0.006(R 2 = 0.9993), as shown in Figure 3. This explains that the glucose control mass concentration has a good linear relationship within the concentration range of 0 to 0.09 mg / mL, and the concentration of the sample can be calculated using this standard graph.

[0049] <Content of mixed pharmaceutical raw materials> <Determining analytical conditions> Figure 4 shows the reaction comparison between the standard solution and the hot water extract. As can be seen from Figure 4, the reaction between the standard solution and the reaction reagent produced a red complex compound, while the sample solution prepared by the hot water extraction method showed no color change after adding the reaction reagent. This explains why the hot water extraction method cannot extract flavonoids from mixed pharmaceutical raw materials. This is because some active ingredients are destroyed under long-term heating conditions, making it impossible to extract the active ingredients or destroying them after extraction.

[0050] Figure 5 compares the extraction efficiency of methanol and ethanol. As can be seen from Figure 5, under ultrasonic conditions, the extraction of flavonoids from mixed pharmaceutical materials using ethanol as the solvent is significantly more effective than using methanol as the solvent. Furthermore, both graphs reach a maximum at 75 minutes, which explains why the flavonoid content of the two solvents is at its highest at 75 minutes. However, the extraction efficiency of ethanol is significantly superior to that of methanol, and the reasons for this need urgent investigation. Therefore, in this experiment, ethanol was used as the pharmaceutical solvent and extraction was performed under ultrasonic conditions for 75 minutes to obtain the solution to be measured.

[0051] <Creating a standard graph> The experiment was carried out as described above, and the corresponding reagent was used as a blank reference. The absorbance was measured at 505 nm, and the linear equation y = 4.761x - 0.044 (R 2 = 0.9989) is obtained. See Figure 6. This shows that the mass concentration of the rutin control sample has a good linear relationship within the concentration range of 0.06 to 0.16 mg / mL, and the sample concentration can be calculated using this standard graph.

[0052] <Polyphenol content in mixed pharmaceutical raw materials> <Determining analytical conditions> Figure 7 shows the optimized reaction conditions for measuring polyphenol content using the Folin phenol method. As can be seen, with increasing reflux time, polyphenol content rises sharply and then begins to decline. This is due to the destruction of active substances as heating time increases. The optimal reflux time, 1.5 hours, is the time required to maximize polyphenol content. After adding the reaction mixture to the sample solution, the mixture was incubated at 50°C for a set period of time, away from direct light. As shown in Figure (b), the reaction was fully completed after 1 hour, resulting in the highest polyphenol content. Thereafter, no significant change in polyphenol content was observed with increasing reaction time. Therefore, the reaction time for this experiment was set at 1 hour. In summary, the optimal method for extracting polyphenol content is to add 50 mL of 60% absolute ethanol, reflux at 80°C for 1.5 hours, cool, and filter through a Büchner funnel. The filtrate is transferred to a 50 mL brown volumetric flask and the volume is adjusted to the graduated line with 60% absolute ethanol to obtain the sample solution. The reaction is carried out sufficiently and the polyphenol content is highest only when the reaction mixture is added to the sample solution and allowed to react for 1 hour at 50°C, avoiding direct light.

[0053] Figure 8 shows the optimization of the reaction solution volume for measuring polyphenol content using the Folin Phenol method. As can be seen from the figure, as the amount of Folin Phenol increases, the measured polyphenol content increases significantly and then begins to decline. The reason for the increase is that as the amount of reaction solution containing polyphenols in the system increases, the reaction becomes more complete. After the reaction is complete, the volume of the solution increases when the reaction solution is added, diluting the polyphenol content and causing the graph to show a downward trend. This is also the reason for the initial rise and then decline in graph (b). In summary, when 4 mL of Folin Phenol and 8 mL of 10% sodium carbonate are added to the solution being measured, the reaction is complete, a peak value appears on the graph, and the polyphenol content reaches its maximum.

[0054] <Creating a standard graph> Perform the experiment as described above. Using the corresponding reagent as a blank reference, develop color in the same way, measure the absorbance at 778 nm, and with the mass concentration on the x-axis and the absorbance on the y-axis, obtain the linear equation y = 6.1302x (R 2 = 0.9991). Refer to Figure 9. This indicates that the mass concentration of the gallic acid reference has a good linear relationship within the concentration range of 0.02 - 0.12 mg / mL, and the sample concentration can be calculated using this standard graph.

[0055] <Optimization Results of the Substrate Composite Blending Ratio in DOE Experiments> <Creation of the Model and Regression Equation> Design the blending ratio of the substrate using DOE in DesignExpert11 software, and measure the mass fractions of polysaccharides, flavonoids, and polyphenols in the substrate under different blending ratios. Refer to Table 2.3 for the design and results of the DOE experiment. Perform a second-order polynomial regression fitting on the test results, construct the Scheffe polynomial regression equation and its analysis of variance model, and create the regression equations for Y polysaccharides, Y flavonoids, and Y polyphenols as follows. Y polysaccharides = 0.1251X1 + 0.2458X2 + 0.1315X3 - 0.1745X1X2 + 0.1185X1X3 - 0.2723X2X3 + 0.2885X1X2X3 Y flavonoids = 0.0842X1 + 0.0814X2 + 0.0623X3 - 0.0383X1X2 - 0.0062X1X3 - 0.0267X2X3 + 0.0470X1X2X3 Y polyphenols = 0.0667X1 + 0.0766X2 + 0.1454X3 + 0.0218X1X2 - 0.0649X1X3 - 0.0834X2X3 - 0.2446X1X2X3

[0056]

Table 3

[0057] From Table 3, the fitting model with the measured polysaccharide fraction as the response value has a p<0.01, which indicates that the model has reached a very significant level and has a good degree of fitting, and that the response surface model can be used for subsequent optimization design. The polysaccharide mass fraction model has a misfit term p>0.10, which indicates that the reproducibility of the experimental results at overlapping points is excellent, and there is not significant difference between the actual experimental results and the model fitting results, which indicates that the model fitting results are reliable and can be used to estimate the experimental results. The correlation coefficient R 2 = 0.9807, which indicates that the model has a good correlation with the actual situation and is suitable for prediction in this experiment. The correlation coefficient after calibration is R 2 Adj = 0.9516, and the data is close to 1, which can well reflect the true experimental value. 2 Pred =0.8002, and the data for both are relatively high and closely matched (R 2 Adj -R 2 Pred The coefficient of variation (CV / %) was 2.85, indicating that the degree of variation was small and reliable. The model well reflects the true experimental values ​​and can be used to analyze and predict the changes in polysaccharide mass fraction in substrates with different formulation ratios.

[0058] [Table 4]

[0059] As can be seen from Table 4, in the analytical model with flavonoid mass fraction as the response value, the parameters are basically similar to those in Table 4. Fitting model p<0.01, misfit term p>0.10, correlation coefficient R 2 =0.9895, and the calibrated correlation coefficient is R 2 Adj =0.9738, and the data is close to 1, so the correlation coefficient for prediction, R 2Pred =0.7930, and the difference between the two (R 2 Adj -R 2 Pred <0.20) was less than 0.20, which met the requirement, and the coefficient of variation (CV / %) was 1.78, which was small and well reflected the true experimental value, and could be used to analyze and predict the changes in flavonoid mass fractions in substrates with different formulation ratios.

[0060] [Table 5]

[0061] Table 5 shows the analysis of variance of the polyphenol mass fraction regression model. Table 6 shows that the parameters of the analysis model using polyphenol mass fraction as the response value are basically similar to those in Tables 3 and 4. The fitting model p<0.01, the lack of fit p>0.10, and the correlation coefficient R 2 =0.9971, and the calibrated correlation coefficient is R 2 Adj =0.9927, and the data is close to 1, so the correlation coefficient for prediction, R 2 Pred =0.9790, and the data for both are relatively high and relatively close (R 2 Adj -R 2 Pred <0.20), and the coefficient of variation was CV / %=1.34, which is small and reflects the true experimental value well, and can be used to analyze and predict the changes in polyphenol mass fractions in substrates with different formulation ratios.

[0062] [Table 6]

[0063] <Effects of different ingredient proportions on physical and chemical properties> Figure 10 shows the contour plot (left) and 3D effect surface (right) of the effect of substrates on polysaccharide mass fraction under different formulation ratios. The sum of the three substrates is 1 and the data range of each component is limited, making the element space complex, which is also why the response surface could not cover the entire triangle in this study. Figure 10 illustrates the effect of different substrate ratios on the polysaccharide mass fraction response. The denser the equipotential lines are in the contour map, the more pronounced the interaction effect. Blue, green, yellow, and red represent low, relatively low, normal, and high response values, respectively. AB, AC, and BC represent the interactions between Dendrobium diffusum / Huang Jing, Dendrobium diffusum / Jujube, and Jujube / Huang Jing. Points a, b, and c indicate the maximum data for Dendrobium diffusum, Huang Jing, and Jujube. For example, point a indicates the Dendrobium diffusum / Huang Jing / Jujube data of 0.85g / 0.10g / 0.05g.

[0064] As can be seen from Figure 10, with increasing amounts of Dendrobium, the trend line (ab) of the effect of Dendrobium / Juiphytum on the response value first decreased and then increased. This explains why, under conditions where the mass fraction of jujube remains constant, as the mass fraction of Dendrobium increases, the polysaccharide content first decreased and then increased. The trend line (ac) of the effect of Dendrobium / Juiphytum on the response value first increased and then decreased. Similarly, under conditions where the mass fraction of Juiphytum remains constant, as the mass fraction of Dendrobium increases, the polysaccharide content first increased and then decreased. Under conditions where the mass fraction of Dendrobium remains constant, as the mass fraction of Juiphytum increases, the trend line (b'c') of the effect of Dendrobium / Juiphytum on the response value first decreased and then increased.

[0065] Figure 10 shows the contour map (left) and 3D effect surface map (right) of the effects of three substrates on flavonoid mass fractions, illustrating the effects of different proportions of substrates on flavonoid mass fractions (response values). Figure 11 shows that with increasing Dendrobium content, the effects of Dendrobium / Yellow Jing and Dendrobium / Jujube on the response values ​​both gradually increased, but the effect of Yellow Jing / Jujube on the response value first increased and then decreased.

[0066] Figure 12 shows the contour plot (left) and 3D response surface (right) of the effects of three substrates on polyphenol mass fraction, illustrating the effect of different proportions of substrates on polyphenol mass fraction (response value). As can be seen from Figure 12, with increasing Dendrobium content, the effect of Dendrobium / Citrus chinensis on the response value first decreased and then increased, while the effects of Dendrobium / Citrus chinensis and Citrus chinensis / Citrus chinensis on the response value both gradually decreased.

[0067] <Recipe optimization and verification experiments> Multi-objective optimization was performed using software, and three recipes were obtained. See Table 7. The mass fractions (%) of Dendrobium chinense, D. chinense, and D. jujube were 84.50 / 10.00 / 5.50 (Recipe 1), 72.20 / 10.00 / 17.80 (Recipe 2), and 55.00 / 40.00 / 5.00 (Recipe 3), respectively. Corresponding points can be found from the contour plots and 3D effect surface diagrams (Figures 10, 11, and 12). Points a, d, and b correspond to Recipes 1, 2, and 3, respectively. The response surface at point a in Figure 10 is significantly lower than point d, which explains why the response value at point a is lower than point d. The response surface at point b is higher than point d, but point b is located on edge AC, which means that the amount of Dendrobium chinense at this point is the lowest. Because this chewable tablet is developed using Dendrobium chinense as the primary ingredient, the formulation ratio at point d is relatively ideal given the actual situation. As can be seen from Figure 11, the response surface at point d is clearly higher than the other two points. As can be seen from Figure 2.12, the response surface at point d is higher than points a and b, so the response value is also higher than the other two points. Looking at the points on the response surface that correspond to the optimal values ​​in Figures 10, 11, and 12, point d is the optimal value.

[0068] Table 7 shows the optimal parameters for the test response values, as well as the predicted and desired values. The closer the desired value is to 1, the better the overall evaluation. Analysis of the optimization results showed that Recipe 2 produced superior results, consistent with the response surface results. Based on this result, it was easier to select experimental points (0.70, 0.10, 0.20) for the experiment and production. Furthermore, the mass fractions of polysaccharides, flavonoids, and polyphenols for this recipe were measured and compared with the predicted values. Table 8 shows a comparison of the actual and predicted values. The results show that the predicted values ​​are close to the test values, demonstrating that the prediction results are reliable.

[0069] [Table 7]

[0070] [Table 8]

[0071] Through regression equation and target optimization analysis, an optimized recipe was obtained, whose mass fraction was 70% Dendrobium sieboldii, 10% Xanthomonas orbiculatus, and 20% Jujube. Verification showed that the mass fraction values ​​of polysaccharides, flavonoids, and polyphenols corresponding to this recipe were 159.60 mg / mL, 79.44 mg / mL, and 78.10 mg / mL, respectively. Each index was consistent with the predicted value, and the goal of optimizing the recipe through physical and chemical indexes was achieved.

[0072] Through the creation of a regression equation and target optimization analysis, the drug substance addition ratio of Dendrobium : Huang Jing : Jujube = (4-8.5): (1-4): (0.5-4) was obtained. Compared to Dendrobium oolong tea (polysaccharide content, polyphenol content, and total flavonoid compound amount were 8.16%, 8.93%, and 36.98%, respectively), the active substance content was higher, and the flavonoid content was higher than that of Dendrobium ginseng fruit wine (flavonoid substance content was 168.1 μg / mL). This explains why the effect of combining Dendrobium with Huang Jing and Jujube is superior to that of combining Dendrobium with oolong tea or ginseng fruit. However, the polysaccharide content detected in this recipe was higher than that of Dendrobium ginseng wine.

[88] The polysaccharide content (12.76%) was lower than that measured directly from Dendrobium stems. This may be due to a certain effect on the polysaccharide content of Dendrobium at different growth ages, or the loss of some active ingredients during Dendrobium product production. The specific causes require further research. Final experimental results showed that the optimized recipe contained high levels of detected active substances. The combined formulation of Dendrobium, Huang Jing, and Jujube was effective, providing more possibilities for compounding Dendrobium products. The final optimized formulation ratio was Dendrobium: Huang Jing: Jujube = (4-8.5):(1-4):(0.5-4). The polysaccharide content of this herbal recipe was 159.64 mg / g, the flavonoid content was 79.44 mg / g, and the polyphenol content was 78.10 mg / g.

[0073] By combining Dendrobium oryzae with Phellodendron amurense and jujube as the main raw materials, selecting appropriate additives, and using direct tableting process, it is possible to research and produce Dendrobium oryzae chewable tablets that are easy to produce, have a sweet and sour taste, are pleasant to eat, and are convenient to carry around.

[0074] 2. Experiment 2: Study on the excipients of Dendrobium chinense chewable tablets by direct compression process <Experimental materials and ritual implements> <Experimental materials>

[0075] Iron peel Shihuo - Leqing City Dagongshan Iron Peel Shihuo Co., Ltd., Huang Jing, Jujube - all of the above ingredients are sourced from Henan Wanbang Chemical Technology Co., Ltd., Erythritol, mannitol, whey protein, magnesium stearate, microcrystalline cellulose - all of the above ingredients are sourced from Henan Wanbang Chemical Technology Co., Ltd., and the above reagents are all food-grade.

[0076] <Experimental Instrument> TDP-1.5 Single Punch Tablet Press - Shanghai Tianhe Co., Ltd., TMS-Pro Texture Analyzer - Stabel Micro System, UK, HBM-109 Ultrafine Particle Mill - Rui'an Hanbo Mechanical & Electrical Co., Ltd., BSA224S-CW Electronic Analytical Balance - Sartorius, Germany, JJ-1 Digital Display Boosting Electric Stirrer - Suzhou Dongpeng Instrument Manufacturing Co., Ltd., DZF-6020 Vacuum Freezing Oven - Shanghai Jinghong Experimental Equipment Co., Ltd.

[0077] <Experimental Method> <Production process of Dendrobium chinense chewable tablets> The additives selected through extensive preliminary experiments include sweeteners, flavoring agents, fillers, and flow aids. Among them, sweeteners (erythritol, mannitol, trichlorosucrose, xylitol) improve the sweetness of the chewable tablets, and flavoring agents (whey protein, peppermint essence)

[92] The additives (oyster-derived peptides) enhance the aroma and flavor of the chewable tablets, the filler (microcrystalline cellulose) adds weight to the tablets and facilitates tableting, and the flow aid (magnesium stearate) improves powder fluidity. Tablet manufacturing process: After washing, the active ingredients are cut and dried with hot air at 100-120°C. After drying, the pharmaceutical ingredients are pulverized in an ultrafine particle mill, and both the pharmaceutical ingredients and excipients are sieved through a 100-mesh sieve. After sieving, the substrates and excipients are uniformly mixed in the proportions specified in the DOE experiments in Chapter 2 and the single-factor or response surface optimization experiments in Chapter 3. Before tableting, 0.50% magnesium stearate is added to the mixed powder and tableted. The resulting chewable tablets are placed in valve bags and stored away from direct light for use.

[0078] <Evaluation criteria for chewable tablets> <Appearance evaluation> National Standard - Sensory Analysis Methodology and Sensory Profile Guidelines (GB / T 39625-2020)

[93] To construct a quantitative descriptive method to analyze the appearance quality of chewable tablets.

[94] The appearance and color of chewable tablets are the evaluation criteria for Dendrobium chinense chewable tablets (see Table 9) based on the definition of oral tablets in (some examples).

[95] The 9-point scale for appearance described in

[2014] was used to create a 9-point scale for this experiment (see Table 10). A food appearance evaluation group consisting of 10 food experts conducted a quantitative technical analysis of the appearance characteristics of the Dendrobium chinense chewable tablets.

[0079] [Table 9]

[0080] [Table 10]

[0081] <Evaluation of mouthfeel> Also referring to GB / T39625-2020

[93] , the mouthfeel characteristics of Dendrobium chinense were used to develop the mouthfeel description terms and evaluation criteria for Dendrobium chinense chewable tablets (Table 11). The evaluation criteria included taste, fineness in the mouth, and tolerance level. The mouthfeel quality of the chewable tablets was analyzed and scored using a quantitative descriptive method. The specific criteria are shown in Table 12. A food appearance evaluation group consisting of 10 food experts scored the mouthfeel of the Dendrobium chinense chewable tablets in Tables 11 and 12. They gargled constantly during the scoring process to prevent any residual taste in the mouth from affecting the evaluation results.

[0082] [Table 11]

[0083] [Table 12]

[0084] <Tablet weight difference measurement> The tablet weight difference measurement for chewable tablets was performed according to the weight difference measurement method in Part 3 (General Rule 0101) of the 2020 version of the Chinese Pharmacopoeia.

[0085] <Hardness measurement> At room temperature, the hardness of the chewable tablets is measured using a texture analyzer. The parameters are TPA mode, P / 2 test probe, stress 50%, and the speeds before, during, and after the test are 6mm / s, 0.5mm / s, and 30mm / s, respectively. Seven parallel tests are carried out for each group, and the maximum and minimum values ​​are excluded to obtain the average value.

[0086] <Selection of additives> <Selection of sweeteners> In this experiment, erythritol, mannitol, trichlorosucrose, and xylitol were used as the initial flavorings for Dendrobium sieboldii chewable tablets. Because trichlorosucrose was too sweet, the maximum amount used was 1g / kg. Therefore, in this experiment, the amounts of trichlorosucrose and other additives were fixed, and a blending ratio experiment was conducted for erythritol, mannitol, trichlorosucrose, and xylitol. See Table 13. The optimal sweetener composition was selected through evaluation of the texture and appearance of the chewable tablets.

[0087] [Table 13]

[0088] <Selection of flavoring agents> Chewable tablets made from traditional Chinese medicines typically have a strong herbal flavor, so flavorings are added to improve the mouthfeel. Recently, researchers have discovered that adding milk powder to the essence can enhance the flavor even more. Whey protein, peppermint essence, and oyster-derived peptides are the most commonly used flavorings in food manufacturing and are often used to mask the off-flavor of ingredients, improve the mouthfeel, and enhance the quality of the ingredients. However, peppermint essence has a strong mint flavor, so the amount added is appropriately reduced. Experiments were conducted with different blend ratios of whey protein, peppermint essence, and oyster-derived peptides while keeping the amounts of other additives constant (see Table 14). The optimal flavoring composition was selected through evaluation of the mouthfeel and appearance of the chewable tablets.

[0089] [Table 14]

[0090] <Selection of acidulants> Generally, adding sweeteners and flavoring agents alone is not enough to mask the inherent bitterness of the active pharmaceutical ingredient. Therefore, an acidulant is added to chewable tablets to mask the unpleasant bitterness of the herbal medicine itself. Lemon acid, also known as citric acid, is commonly used as an acidulant and has excellent effects in masking salty and bitter tastes. Therefore, citric acid was used as the acidulant in this experiment. The amounts of other additives were fixed, and citric acid was added at 0.5%, 0.6%, 0.7%, 0.8%, and 0.9%. The optimal acidulant was selected based on the extent to which it could mask the sourness and bitter aftertaste of the chewable tablets.

[0091] <Single-factor experiment> The total powder weight of the active ingredient dose was fixed, and the effects of different amounts of erythritol, mannitol, and whey protein on chewable tablets were investigated using appearance, mouthfeel, weight difference, and chewable tablet hardness as indicators (when investigating a single factor, the other factors took intermediate values).

[0092] <Effect of erythritol on Dendrobium sieboldii chewable tablets> In this experiment, the erythritol addition amount was set to 5%, 10%, 15%, 20%, and 25%, and the effect of the five gradient addition amounts on Dendrobium ferruginosa chewable tablets was investigated to select the optimal interval of the response surface.

[0093] <Effect of mannitol on Dendrobium sieboldii chewable tablets> In this experiment, the effects of mannitol on Dendrobium ferrocene chewable tablets were investigated at five gradients of mannitol addition levels: 5%, 10%, 15%, 20%, and 25%, and the optimal response range was selected.

[0094] <Effect of whey protein on Dendrobium chinense chewable tablets> In this experiment, the whey protein addition amount was set to 3.5%, 4.5%, 5.5%, 6.5%, and 7.5%, and the effects of five graded addition amounts on Dendrobium ferruginosa chewable tablets were examined to select the optimal interval of the response surface.

[0095] <Analysis of powder properties before tableting> <Powder fluidity analysis> The angle of repose is one of the most commonly used methods for measuring the fluidity of powders, and it mainly reflects the frictional force between particles. The smaller the angle of repose, the better the fluidity. To display it, pile the powder into the shape of a cone as steep as possible, and then use the included angle between the hypotenuse and the horizontal line as the angle of repose.

[0096] Measure using the fixed funnel method; see Figure 13. Fix three funnels in series on an iron stand, polish the bottom outlet flat, and place a piece of coordinate paper 1 cm from the bottom opening. Slowly pour the prepared granules along the top funnel wall until the particles piled up on the seat cover reach the tip of the cone at the funnel opening. Measure the diameter of the bottom of the cone using the scale marked on the coordinate paper, and calculate the angle of repose. See (3-1) for the calculation formula. (Measure five times repeatedly) and take the average value.

[0097]

number

[0098] <Powder compressibility analysis> Pour a known weight of sample into a measuring cylinder, measure the volume of that weight, and tap gently until the volume does not change. Calculate the powder pile volume, density (Ptap) and packed density (Pbulk) according to the initial weight, initial volume, and packed volume. See formulas (3-2) and (3-3). Determine the compressibility index. See formula (3-4) for Carr's index (CI). Average the measurements (5 times).

[0099]

number

[0100] <Determining weighting factors> The response surface test optimization index is the composite score of four indexes: appearance score (a), mouthfeel score (b), tablet weight difference (c), and hardness (d). The higher the appearance score, the better the mouthfeel; therefore, the larger the data for a and b, the better. The smaller the tablet weight difference, the better; c is an inverse index, the smaller the better. For ease of transportation and chewing, the tablet hardness should be 15N or greater, and d should be larger the better. Considering the index requirements and their contribution to compactibility, the indexes are nondimensionalized and a comprehensive evaluation is performed. Weight difference is an inverse index, and is treated as a positive index using the reciprocal method. Table 15 shows the comprehensive evaluation method for multiple indexes. The comprehensive evaluation is calculated by adding up the values ​​of each index.

[0101] [Table 15]

[0102] Determining the optimal recipe for chewable Dendrobium sieboldii tablets using response surface optimization The optimum range of additives was selected by single-factor testing, and a Box-Behnken test design was used with different mass fractions of erythritol (A), mannitol (B), and whey protein (C) as independent variables (see Table 16). A three-factor, three-level response surface optimization test was conducted using the comprehensive evaluation of the chewable tablets, consisting of appearance evaluation, mouthfeel evaluation, hardness, and weight difference, as indicators. Through the optimization of the recipe additives, the optimal additive blending ratio of Dendrobium ferruginosa chewable tablets was obtained.

[0103] [Table 16]

[0104] <Data processing> All experiments were repeated three times after sample preparation, and the average of the three measurements was taken. The final results were analyzed using Excel, plotted using Origin2021 software, and then polynomial regression fitting, analysis of variance, and significance analysis were performed twice on the data using Design-Expert11 software.

[0105] <Results and Analysis> <Additive selection results> <Sweetener selection results> The results of the sweetener interactions are shown in Table 17. Figure 14 shows the finished chewable tablets manufactured with different sweetener ratios. As can be seen from Table 17 and Figure 14, the addition of xylitol makes the chewable tablets too dark in color and causes cracking. Therefore, xylitol was not selected as the sweetener in this experiment. Erythritol improves the taste of the chewable tablets, enhancing their sweetness while also providing a refreshing sensation in the mouth. Although mannitol contributes less to improving sweetness than erythritol, the addition of mannitol significantly improves the appearance of the chewable tablets, making them smooth and glossy, and also increasing their hardness. This may be related to the fact that mannitol improves powder flowability. Therefore, erythritol, mannitol, and trichlorosucrose were selected as the sweeteners in this experiment. Since the addition of erythritol and mannitol has a significant effect on improving the mouthfeel and appearance of the chewable tablets, further single factor experiments on the amount of erythritol and mannitol added will be carried out.

[0106] [Table 17]

[0107] <Negative control> The substrate ratios were different, and no additives were added. The substrate ratio was: Dendrocta: Jujube: Yellow Jelly = 4:4:2 (Figure 15(a)). Evaluation: The quality was soft, prone to cracking, difficult to shape, and the surface was rough. The substrate ratio was: Dendrocta: Jujube: Yellow Jelly = 7:2:1 (Figure 15(b)). Evaluation: The quality was soft, prone to cracking, difficult to shape, and the surface was rough. The substrate ratio was: Dendrocta: Jujube: Yellow Jelly = 85:5:10 (Figure 15(c)). Evaluation: The quality was soft, prone to cracking, difficult to shape, and the surface was rough.

[0108] Only additives, no substrate. Evaluation of Figure 15(d): Easy to crack and difficult to mold.

[0109] <Flavoring agent selection results> See Table 18 for specific results of the interaction between flavoring agents. As can be seen from Table 18, whey protein, peppermint extract, and oyster-derived peptides have a synergistic effect, and adding these three flavoring agents simultaneously will enhance the aroma of chewable tablets. Therefore, whey protein, peppermint extract, and oyster-derived peptides are used as flavoring agents for chewable tablets. In the experiment, the addition of whey protein gave the chewable tablets a faint milk aroma, significantly improving the aroma of the chewable tablets. Therefore, different amounts of whey protein were added and further single-factor experiments were conducted.

[0110] [Table 18]

[0111] <Results of acidulant selection> The citric acid dosage was selected, as shown in Table 19. As the amount of acidulant increased, the bitter aftertaste in the chewable tablets was gradually masked. When the amount of citric acid added reached 0.80%, the effect of masking the bitter aftertaste was obvious and the acidity was appropriate. When the amount of citric acid added reached 0.90%, the chewable tablets became too sour in the mouth and were unacceptable. Therefore, in this experiment, the amount of citric acid added was set to 0.80%.

[0112] [Table 19]

[0113] <Single factor experiment results> <Effect of erythritol on Dendrobium sieboldii chewable tablets> Table 20 is an analysis of variance table for erythritol mass fraction. As can be seen from the table, different amounts of erythritol added have a significant effect on the appearance, mouthfeel, and hardness of the chewable tablets, as well as a significant effect on weight variance. As the erythritol mass fraction increases, the specific evaluation indexes change as shown in Figure 16. Figure 16 is a graph showing the effect of erythritol mass fraction on the mass of Dendrobium sieboldii chewable tablets. As can be seen from the graph, with increasing erythritol mass fraction, the appearance evaluation first improved significantly and then slowly decreased, reaching a maximum at a mass fraction of 15.00%. The mouthfeel first gradually increased and then decreased, reaching the best at 15.00%. This is because erythritol increases the sweetness and refreshing feeling of the chewable tablets. However, if too much erythritol is added, the tablets will be too sweet. The weight variance decreased significantly at a mass fraction of 10.00%, and then gradually decreased. The hardness increased slowly, due to the good fluidity and compressibility of erythritol, making it easy to tablet. Furthermore, because the dosage of this drug is high, it is desirable to minimize the amount of additive used while achieving the same effect. In summary, the response surface optimization interval is 10.00-15.00% erythritol mass fraction.

[0114] [Table 20]

[0115] <Effect of mannitol on Dendrobium sieboldii chewable tablets> Table 21 shows the analysis of variance for mannitol mass fraction. As can be seen, different amounts of mannitol have a significant effect on the appearance, mouthfeel, hardness, and weight variation of chewable tablets. See Figure 17 for the specific changes in evaluation indexes as the mannitol mass fraction increases. Figure 16 shows the effect of mannitol mass fraction on Dendrobium ferruginosa chewable tablets. As can be seen from Figure 16, the appearance score gradually increases with increasing mannitol content. This is because mannitol has good compressibility. As the amount of mannitol increases during direct compression, the chewable tablet surface becomes smoother, resulting in a higher appearance score. The mouthfeel first increases significantly and then stabilizes, reaching a peak when the mass fraction is between 11.00% and 15.00%. This is due to the faint sweetness of mannitol. At relatively low mass fractions, the sweetness changes significantly, after which it stabilizes. As the mannitol content increases, the weight difference of the chewable tablets first decreases rapidly and then gradually decreases. This is because mannitol improves the fluidity of the matrix powder mixture, improving its compressibility. The hardness of the chewable tablets first increases significantly and then increases slowly. The appearance and hardness of the chewable tablets also increase with increasing mannitol content. The mouthfeel scores reach a maximum at mass fractions of 11.00% to 15.00%. The weight difference scores reach a minimum at mass fractions of 11.00% to 15.00% and 25.00%, and the data are closely matched. In summary, the mannitol mass fraction range of 11.00% to 15.00% is the optimized region of the mannitol response surface.

[0116] [Table 21]

[0117] <Effect of whey protein on Dendrobium chinense chewable tablets> Table 22 shows the analysis of variance for whey protein mass fraction. As can be seen, different amounts of whey protein added have a significant effect on the appearance, texture, and weight variance of the chewable tablets, as well as their hardness. See Figure 18 for the specific changes in evaluation indicators as the whey protein mass fraction increases. Figure 18 shows the effect of whey protein mass fraction on the mass of Dendrobium ferruginosa chewable tablets. As can be seen from Figure 18, as the whey protein content increases, both the appearance and texture of the chewable tablets improve, reaching their maximum values ​​at 5.50% and 6.50-7.50%, respectively. The weight variance is at its minimum when the mass fraction is 6.50%. Increasing whey protein slowly increases the hardness of the chewable tablets. In summary, while maintaining the same effect, the principle is to use as little additives as possible, and the optimal response area is found to be between 5.50% and 6.50% whey protein mass fraction.

[0118] [Table 22]

[0119] <Measurement results of powder properties> <Powder fluidity measurement results> Five lots of uncompressed powder were randomly selected and numbered, and then flowability tests were carried out, the results of which are shown in Table 23.

[0120] [Table 23]

[0121] The angle of repose is used as an index for powder fluidity, and the angles of repose measured for all five lots of uncompressed powder were less than 30°. This is because the addition of additives improves the fluidity of the uncompressed powder and increases its compressibility.

[0122] <Measurement results of powder compressibility> Five batches of uncompressed powder were randomly selected and numbered, and then a compressibility test was conducted. The compressibility measurement results of the five batches of powder are shown in Table 24.

[0123] [Table 24]

[0124] Carr's index is used as an index for compressibility, and the angles of repose measured from the five lots of uncompressed powder were all less than 15%, which explains why the addition of additives improved the compressibility of the powder.

[0125] <Optimal recipe for chewable tablets of Dendrobium chinense using response surface optimization:> Table 25 shows the Box-Behnken experimental design and results. A three-factor, three-level response surface design was performed using Design Expert software, and 5 core points were selected to perform a total of 17 sets of tests. Table 26 shows the quadratic regression analysis of variance for the Box-Behnken test results. As can be seen from the table, p<0.01 for the model indicates that the model is highly significant and can predict the true relationship between each factor and the response surface. This model can be used to determine the tableting excipient recipe. The non-conformance term p>0.01 is not significant, indicating that the experimental results for the duplicated points are well reproducible and there is not significant difference between the actual results and the predicted results. The correlation coefficient R of the model 2 = 0.9773, which indicates that the model has a good fitting effect and is suitable for the prediction of this test. 2 Adj=0.9480, which indicates that the model accurately reflects the true test values. Among them, the primary simulation terms A and B and the secondary simulation terms A2 and B2 had a significant effect on the results (p<0.01), which indicates that these indicators had a significant impact on the evaluation indicators of this experiment. The secondary simulation term C2 and the interaction term AB had a significant effect on the results (p<0.05), which indicates that they had a certain impact on the evaluation indicators of this experiment. The primary simulation term C and the interaction terms AC and BC had no significant effect on the results (p>0.01).

[0126] [Table 25]

[0127] [Table 26]

[0128] Figure 19 is a 3D response surface diagram showing the effect of erythritol and mannitol mass fractions on the overall evaluation, with the lines at the bottom of the diagram being contour lines. As can be seen from the diagram, the response surface is curved and has a large degree of curvature. This explains the significant interaction between A and B, which is consistent with the analysis of variance results. The contour lines in the diagram form a circle, which explains the peaks on the diagram. The response value reaches its maximum when the erythritol mass fraction is approximately 11.50-14.00% and the mannitol mass fraction is 13-15%.

[0129] Figure 20 is a 3D response surface diagram showing the effects of erythritol and whey protein mass fraction on the overall evaluation. The lower lines in the diagram are contour lines. As can be seen from Figure 20, the response surface is a curved surface, illustrating the interaction between erythritol and whey protein. Furthermore, as can be seen from the diagram, when the A value is constant, the curvature of the response surface changes little as the B mass fraction increases. However, when the B value is constant, the curvature of the response surface changes greatly as the A mass fraction increases. This explains why the A value has a large effect on the response value, while the B value has a small effect on the response value. This conclusion is consistent with the analysis results in Table 27. The contour lines in the diagram form an ellipse, indicating the presence of a peak on the diagram. The corresponding values ​​reach their maximum values ​​when the A and C values ​​are between 12.50% and 14.50%, and between 5.90% and 6.10%, respectively, consistent with the results of the response surface diagram.

[0130] Figure 21 is a 3D response surface diagram showing the effect of mannitol and whey protein fraction on the overall evaluation. The lower lines in the diagram are contour lines. As can be seen from Figure 21, the response surface is curved, so there is an interaction between B and C. The contour lines in the diagram form an ellipse, and a peak appears on the diagram. The peak appears when the mannitol mass fraction is between 13.50% and 14.50%, and the whey protein mass fraction is approximately between 5.90% and 6.10%.

[0131] Optimization was performed using a software optimization program. The results showed that when the mass fractions of erythritol, mannitol, and whey protein were 13.20%, 13.29%, and 6.01%, respectively, the model's overall score was 21.61, consistent with the 3D response surface results. Considering actual operation, the mass fractions of the three components were slightly adjusted to 13.00%, 13.00%, and 6.00%. Using the optimized mass fractions, three replicate tests were performed. The measured external appearance score of Dendrobium chewable tablets was 7.8±0.6 points, the mouthfeel score was 7.8±0.4 points, the hardness and weight difference were 23.72±0.15 N and 2.57±0.13%, respectively. The average overall score was 21.87±0.83 points, consistent with the predicted values.

[0132] Currently, only Dendrobium chewable tablets are evaluated, using sensory scoring as the evaluation index. For Monk's Ginseng chewable tablets, Nutmeg chewable tablets, and Nizatidine chewable tablets, only objective factors such as chewable tablet weight difference, hardness, and powder flowability are used as evaluation indexes. However, because chewable tablets are only ingested after being chewed in the mouth and then broken into particles that are easy to swallow, subjective factors are also important in the evaluation of chewable tablets. A single subjective or objective evaluation cannot accurately reflect the quality of chewable tablets. Only a comprehensive evaluation of chewable tablet quality can be achieved by combining subjective and objective factors. The experiments in this section combine single-factor experiments with multi-index weighted response surface optimization to select and optimize chewable tablet excipients using appearance, mouthfeel, weight difference, and hardness as evaluation indexes.

[0133] To sum up, The present invention unexpectedly discovered that under the recipe of adding the raw materials in the proportion of Dendrobium chinense:Cucurbitaceae:Jujube=(4-8.5):(1-4):(0.5-4), the content of active substances detected in the medicine was high, which is due to the combined effect of Dendrobium chinense,Cucurbitaceae and Jujube, which has a synergistic effect on the active ingredients.

[0134] The present invention unexpectedly discovered that the sweetener recipe, a combination of erythritol, trichlorosucrose, and mannitol, has a synergistic effect on the molding and mouthfeel of chewable tablets. The chewable tablets produced using the recipe of the present invention and direct compression method all had excellent overall indicators such as appearance, mouthfeel, hardness, and weight difference.

[0135] The final optimized recipe is Dendrobium 20%-42.50%, Xanthomonas chinensis 5.00%-20%, Jujube 2.50%-20.00%, Erythritol 5.00%-25.00%, Mannitol 5.00%-25.00%, Whey protein 5.00%-7.50%, Oyster peptide 1.00%-4.00%, Mint extract 0.50%-2.50%, Citric acid 0.50%-1.00%, Trichlorosucrose 0.05%-0.25%, Magnesium stearate 0.05%-1.00%, Microcrystalline cellulose 7.50%-15.00%. This recipe has a stable process and the product has excellent appearance and mouthfeel, high hardness, and small weight variation.

[0136] <Comparison of mixed tableting of substrate and excipients with different mixing ratios>

[0137] [Table 27] JPEG2025173923000032.jpg156170

[0138] The substrate and additives are mixed according to the above proportions and then compressed into tablets. Although different proportions of substrate and additives can be used, the appearance and hardness of the chewable tablets will be affected depending on the mixing proportion. Therefore, the optimal mixing proportion of the substrate and additives is determined by comprehensively evaluating indicators such as the content of the active substance, mouthfeel, appearance, tablet weight difference and hardness.

[0139] The above has described the basic principles, main features and advantages of the present invention. However, those skilled in the art should understand that the above embodiments do not limit the present invention in any way, and any technical means obtained by equivalent substitution or equivalent conversion are all within the scope of protection of the present invention.

Claims

1. A chewable tablet of Dendrobium chinense, characterized in that Dendrobium chinense: Phellodendron amurense: Jujube are mixed in a mass ratio of (4-8.5):(1-4):(0.5-4).

2. The Dendrobium iron oxide chewable tablet of claim 1, further comprising a sweetener, a flavoring agent, a filler and a flow aid, wherein the sweetener is one or a combination of erythritol, mannitol, trichlorosucrose or xylitol, the flavoring agent is one or a combination of whey protein, peppermint essence or oyster-derived peptide, the filler is microcrystalline cellulose, and the flow aid is magnesium stearate.

3. The chewable tablet of Dendrobium orthosilicate according to claim 2, characterized in that the sweetener is a composition of erythritol, mannitol and trichlorosucrose.

4. 2. The Dendrite chewable tablet according to claim 1, characterized in that the composition by mass fraction is Dendrite 20%-42.50%, Xanthomonas Root Extract 5.00%-20%, Jujube 2.50%-20.00%, Erythritol 5.00-25.00%, Mannitol 5.00-25.00%, Whey Protein 5.00-7.50%, Oyster-derived peptide 1.00-4.00%, Peppermint essence 0.50-2.50%, Citric acid 0.50-1.00%, Trichlorosucrose 0.05-0.25%, Magnesium stearate 0.05-1.00%, Microcrystalline cellulose 7.50-15.00%.

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