A kind of dihydroquercetin composite effervescent tablet and preparation method thereof

Abstract

The present invention provides a dihydroquercetin composite effervescent tablet and a preparation method thereof. The effervescent tablet adopts sodium hyaluronate or xanthan gum as a stabilizer, and the specific formula is as follows: 0.1%-0.3% of dihydroquercetin, 0-0.6% of stabilizer, 0.3%-1.5% of complex vitamins, 0.02%-0.1% of complex minerals, 15%-30% of fillers, 0.5%-1% of sweeteners, 0-30% of lactose, 10%-30% of alkali sources, 25%-40% of acid sources, 1%-2% of flavors, and the sum of the mass percentages of the components is 1. Lactose can also be replaced by glucose or mannose. When the stabilizer is sodium hyaluronate, the corresponding mass percentage is 0.2%-0.6%. The dihydroquercetin effervescent tablet provided by the present invention adopts lactose to promote the disintegration of the effervescent tablet; the present invention forms a polymer by sodium hyaluronate, xanthan gum and dihydroquercetin, thereby increasing the solubility of dihydroquercetin in water; the present invention also enhances the thermal stability of sodium hyaluronate in an acidic aqueous solution.

Description

Technical Field

[0001] The invention relates to the field of food, and in particular to a dihydroquercetin composite effervescent tablet and a preparation method thereof. Background Art

[0002] Dihydroquercetin, also known as Taxodium indica, Taxodium indica, and Taxodium indica, is a bioflavonoid quasi-vitamin P. Dihydroquercetin is widely found in various plants, and its content is relatively high in larch. Dihydroquercetin can be used not only as an antioxidant for vegetable oils and vegetable fats, but also as a substance with the properties of vitamin P, with significant anti-inflammatory, antihistamine and radiation protection effects.

[0003]

[0004] The strong oxidizing property of dihydroquercetin makes it suitable for use in the food field as a good food-grade antioxidant ingredient. Dihydroquercetin is not easily soluble in cold water but is soluble in various vegetable oils. Therefore, it is often used in the production of oils and fat-containing products, such as cream, cheese, milk powder, margarine, etc. In 2018, the European Commission issued Regulation No. 2017 / 461, and dihydroquercetin extract entered the EU market as a new food ingredient. In 2021, the National Health Commission issued an announcement on the use of dihydroquercetin as a new food ingredient, with a recommended consumption of ≤100 mg / day. There are relatively few research reports on dihydroquercetin as a food ingredient, and most reports focus on its medicinal value.

[0005] The solubility of dihydroquercetin in water is low. The solubility results of dihydroquercetin standard in different solvents in "Study on the Extraction, Identification and Antioxidant Activity of Dihydroquercetin in Larch" (2011, Harbin Normal University) show that the solubility of dihydroquercetin in water is less than 2g / 100g solvent, which is much lower than the solubility in organic solvents such as acetone, ethanol, and methanol. When taking dihydroquercetin effervescent tablets orally, they need to be brewed with cold or warm water. The solubility of dihydroquercetin in the corresponding effervescent tablet aqueous solution is low, and it cannot better play an antioxidant role.

[0006] As the main component of the extracellular matrix, sodium hyaluronate is widely distributed in connective tissues such as the skin, vitreous body, umbilical cord, cartilage and synovial fluid, and has physiological functions such as moisturizing, lubricating, nourishing, repairing and preventing damage. In 2021, sodium hyaluronate was officially approved as a "new food ingredient" to be added to ordinary foods. Applicable food categories include dairy products, beverages, candies, frozen drinks, etc. In edible products, sodium hyaluronate has the effects of increasing skin moisture and improving cardiovascular health. However, the stability of sodium hyaluronate is not good. "Research on the Thermal Stability of Sodium Hyaluronate" (Food and Drug, 2006, 8(01): 29-33) shows that sodium hyaluronate degrades rapidly under acidic aqueous solution conditions, and the higher the acidity, the faster the degradation rate. Increasing the stability of sodium hyaluronate in acidic aqueous solution is of great significance to improving the quality of sodium hyaluronate products.

[0007] Direct powder compression refers to a preparation process in which a powder mixture of active pharmaceutical ingredients and excipients is directly compressed into tablets without granulation pretreatment. It has low production cost, high efficiency, good product quality, and is increasingly widely used. The existing direct powder compression of effervescent tablets adds lubricants to reduce the occurrence of sticking; and adds disintegrants to shorten the disintegration time.

[0008] "Preparation process optimization and quality analysis of bamboo leaf extract effervescent tablets" (Food Science, 2016, 37(8): 39-44) uses polyethylene glycol 6000 as a lubricant for direct powder compression to prepare bamboo leaf extract effervescent tablets. Among them, the mass fraction of citric acid is 20%, the mass fraction of sodium bicarbonate is 20%, and the sodium bicarbonate is coated with polyethylene glycol 6000. Polyethylene glycol coating of part of the effervescent agent mainly affects the hardness of the effervescent tablet, and can prevent the main ingredients from directly contacting with citric acid and deteriorating.

[0009] "Preparation Method of Pediatric Asthma Effervescent Tablets" (Central South Pharmacy, 2008, 6 (3): 315-317) uses cross-linked polyvinyl pyrrolidone as a disintegrant, polyvinyl pyrrolidone as a binder, and polyethylene glycol 6000 as a lubricant. In the article, after adding drug powder, excipients, and lubricants to tartaric acid and CO2 sources, mixing, and tableting, the effervescent tablets are not sticky and have good hygroscopicity. Although the use of lubricants in effervescent tablets can reduce sticking, increasing the lubricant content will increase the hardness of the tablets and prolong the disintegration time. Therefore, it is necessary to add disintegrants at the same time to shorten the disintegration time. The addition of lubricants and disintegrants will reduce the content of active ingredients in the unit tablet and increase the production cost of the finished effervescent tablets.

[0010] Therefore, the market urgently needs to develop a dihydroquercetin composite effervescent tablet that increases the water solubility of dihydroquercetin, the stability of sodium hyaluronate, has a high content of active ingredients per unit tablet and a faster disintegration rate. Summary of the invention

[0011] The invention provides a dihydroquercetin composite effervescent tablet, which further comprises composite vitamins, composite minerals, sodium hyaluronate or xanthan gum, has good water solubility and stability of dihydroquercetin, can be quickly disintegrated within 3 minutes, and can better solve the technical problem of poor disintegration in the direct compression preparation process of the effervescent tablet without adding a lubricant and a disintegrant.

[0012] The invention provides a dihydroquercetin composite effervescent tablet, characterized in that the effervescent tablet is composed of the following components and their mass percentages: 0.1%-0.3% of dihydroquercetin, 0-0.6% of stabilizer, 0.3%-1.5% of composite vitamins, 0.02%-0.1% of composite minerals, 15%-30% of fillers, 0.5%-1% of sweeteners, 0-30% of lactose, 10%-30% of alkali sources, 25%-40% of acid sources, and 1%-2% of flavors, and the sum of the mass percentages of the components is 1. The stabilizer is sodium hyaluronate or xanthan gum.

[0013] Furthermore, lactose may be replaced by glucose or mannitol.

[0014] Furthermore, the stabilizer is sodium hyaluronate, and the corresponding mass percentage is 0.2%-0.6%.

[0015] Furthermore, the mass percentage of lactose is 15%-30%.

[0016] Furthermore, the compound vitamins include one or more of vitamin C, vitamin D, vitamin E, vitamin B1, vitamin B2, vitamin B12, niacin, folic acid, and pantothenic acid. The compound minerals include iron ions and zinc ions, wherein the iron ions include one or two of ferrous gluconate and ferrous fumarate, and the zinc ions include one or more of licorice zinc, zinc citrate, and zinc gluconate. The content of each vitamin component in the compound vitamins and the content of each mineral component in the compound minerals meet the national standards for the use of food nutrient enhancers.

[0017] Furthermore, the filler includes one or more of erythritol, sorbitol, and mannitol.

[0018] Furthermore, the sweetener is one or more of sucralose, saccharin sodium, acesulfame potassium or steviol glycoside.

[0019] Furthermore, the alkali source is sodium bicarbonate, the acid source is one or more of citric acid, tartaric acid or malic acid, and the mass ratio of the alkali source to the acid source is 0.4:1-0.7:1.

[0020] The present invention also provides a method for preparing the dihydroquercetin composite effervescent tablet, the preparation method comprising the following steps:

[0021] (1) Weighing raw materials other than lactose according to the formula, mixing, and crushing through a 100-mesh sieve;

[0022] (2) weighing 30-40 mesh lactose according to the formula, and adding it and the raw materials in step (1) into a mixer in equal amounts in multiple times, and mixing until the material has a uniform color and texture;

[0023] (3) Tablets were compressed using a tablet press and the weight difference of the tablets was checked. The hardness of the obtained tablets was 36N-46N.

[0024] The present invention adopts a powder direct compression preparation process. The premise of applying the powder direct compression process is that the material mixing uniformity is good, and the particle size and distribution of each material are key factors affecting the mixing effect, and the stability of the acid source and the alkali source is required to be higher. The dihydroquercetin effervescent tablet provided by the present invention uses lactose to promote the disintegration of the effervescent tablet. On the one hand, lactose can act as a filler to block the acid source and the alkali source during the mixing process and increase the stability of the disintegrant; on the other hand, lactose has a disintegration-promoting effect, dissolves quickly after encountering water, and the acid source and the alkali source are fully in contact to accelerate disintegration. The disintegration time of the dihydroquercetin effervescent tablet provided by the present invention is about 3 minutes. Compared with the effervescent tablets without adding lactose, the disintegration time is shortened by more than 60%; compared with the effervescent tablets with other sweeteners such as glucose and mannose, the disintegration time is shortened by more than 33%.

[0025] In addition, the present invention forms a polymer with sodium hyaluronate, xanthan gum and dihydroquercetin, thereby increasing the solubility of dihydroquercetin in water; the present invention also enhances the thermal stability of sodium hyaluronate in an acidic aqueous solution. The dihydroquercetin composite effervescent tablet formulation of the present invention solves the problems of poor solubility of dihydroquercetin and poor stability of sodium hyaluronate during the dissolution of the effervescent tablet.

[0026] The advantages of the present invention are:

[0027] (1) The present invention uses lactose to solve the problem of poor uniformity and stability of direct mixing of acid source and alkali source in the powder direct compression preparation process. Without adding lubricants or disintegrants, the disintegration time of the effervescent tablet is greatly shortened and the tablet is not sticky.

[0028] The disintegration time of the effervescent tablets 1 to 5 prepared by lactose of the present invention is less than 3.1 minutes; after removing lactose from effervescent tablet 2, the sorbitol content is increased and the ratio of sodium bicarbonate to citric acid is adjusted to obtain effervescent tablet 8, and the disintegration time is 7.8 minutes, which is more than 2.5 times the disintegration time of the effervescent tablet of the present invention. After replacing the lactose in effervescent tablet 2 with glucose and mannose, effervescent tablets 9 and 10 are obtained, and the disintegration times are 5.6 minutes and 4.2 minutes, respectively, which are 1.5 to 2 times the disintegration time of the effervescent tablet of the present invention. It can be seen that lactose as a filler of the present invention has a better disintegration effect than similar sugars.

[0029] Effervescent tablets 6 and 7 were prepared using a formulation outside the scope of the present invention, wherein the disintegration time of effervescent tablet 6 was 6.4 min, which was more than twice the disintegration time of the effervescent tablet within the scope of the present invention, and effervescent tablet 7 could not be formed. The reason is that when the effervescent tablet is prepared by direct powder compression, high requirements are placed on mixing uniformity, compressibility of auxiliary materials, fluidity, etc., and the use of unreasonable types or contents of auxiliary materials has a great influence on the tablet forming, disintegration, etc.

[0030] Effervescent tablet 11 is obtained by removing sodium hyaluronate from effervescent tablet 2, and effervescent tablet 12 is obtained by replacing sodium hyaluronate in effervescent tablet 2 with xanthan gum. The corresponding disintegration times of the two are not much different from those of effervescent tablet 2, and are both better than effervescent tablets 6 to 10. The reason is that sodium hyaluronate accounts for a small proportion in the effervescent tablet and has little effect on lactose-promoted disintegration.

[0031] The effervescent tablets 1-5, 11-12 protected by the present invention use lactose as an auxiliary material, and have specificity in the selection of the types and contents of the corresponding formulation ingredients. Without adding lubricants and disintegrants, the technical problem of poor disintegration in the direct compression preparation process of the effervescent tablets can be better solved.

[0032] Table 1 Hardness and disintegration time of effervescent tablets

[0033] sample Hardness(N) Disintegration time (min) Effervescent tablet 1 44 3.0 Effervescent tablets 2 46 2.8 Effervescent tablets 3 40 3.1 Effervescent tablets 4 46 2.4 Effervescent tablets 5 42 2.4 Effervescent tablets 6 55 6.4 Effervescent tablets 7 Cannot be formed / Effervescent tablets 8 40 7.8 Effervescent tablets 9 26 5.6 Effervescent tablets 10 36 4.2 Effervescent tablets 11 44 2.5 Effervescent tablets 12 42 2.4

[0034] (2) The present invention uses sodium hyaluronate and xanthan gum as solubilizing components of the effervescent tablet, which solves the problem of poor solubility of dihydroquercetin effervescent tablets in water, increases the dissolution of effective ingredients during the administration of the effervescent tablet, and promotes human absorption.

[0035] The inventor of this patent found in the research process that the dissolution transfer rate of dihydroquercetin in the dihydroquercetin water-soluble sample is only 76%, and the dissolution transfer rate = dihydroquercetin content after dissolution / theoretical value of dihydroquercetin content*100%. The higher the dissolution transfer rate, the better the solubility. Literature search found that the solubility of dihydroquercetin in water is less than 2g / 100g solvent. Because dihydroquercetin effervescent tablets need to be taken with water during administration, increasing the dissolution transfer rate of dihydroquercetin can better exert the antioxidant effect of the product.

[0036] The dissolution transfer rate of the effervescent tablets 1 to 5 prepared by using sodium hyaluronate as a solubilizer for dihydroquercetin is 90% to 92.5%, which is much higher than the dissolution transfer rate of the water-soluble dihydroquercetin sample of 76%. Effervescent tablets 8 to 10 are the lactose-substituted control group corresponding to Example 2, and the corresponding dissolution transfer rate is about 92%, which shows that the excipient lactose has little effect on the dissolution transfer rate of dihydroquercetin.

[0037] Effervescent tablet 6 is a prescription outside the protection scope of the present invention, and its dihydroquercetin dissolution transfer rate is not detected. Through prior art search and analysis, it is found that the characteristic absorption peak of dihydroquercetin does not change substantially under acidic conditions, but as the pH value increases, the characteristic peak absorption wavelength increases significantly and the solution color changes, and dihydroquercetin may be degraded. The pH value of effervescent tablet 6 after dissolution is 5.5, and dihydroquercetin is not detected due to the displacement of the characteristic peak. As can be seen from the above, the prescription of effervescent tablet 6 cannot promote the improvement of dissolution transfer rate under the premise of ensuring the antioxidant effect of dihydroquercetin.

[0038] The present invention also provides a sodium hyaluronate tasteless control effervescent tablet 11 of the effervescent tablet 2, and an effervescent tablet 12 in which sodium hyaluronate is replaced by xanthan gum. The dissolution transfer rate comparison shows that the dissolution transfer rate of the effervescent tablet 11 is similar to that of the dihydroquercetin water-soluble sample, which shows that sodium hyaluronate in the dihydroquercetin effervescent tablet of the present invention is the main component that promotes the dissolution of dihydroquercetin. The dissolution transfer rate of the effervescent tablet 12 is similar to that of the effervescent tablet 2, which shows that both sodium hyaluronate and xanthan gum have the effect of promoting the dissolution of dihydroquercetin.

[0039] The effervescent tablets 1 to 5, 8 to 10 and 12 protected by the present invention use sodium hyaluronate and xanthan gum to increase the dissolution transfer rate of dihydroquercetin, which can be better absorbed by the human body and exert the antioxidant effect of the product.

[0040] Table 2 Dissolution transfer rate and pH value of effervescent tablets

[0041] Group Dissolution transfer rate (%) pH Effervescent tablet 1 92.5 4.7 Effervescent tablets 2 91.5 4.3 Effervescent tablets 3 90.2 4.5 Effervescent tablets 4 91.1 4.3 Effervescent tablets 5 92.0 4.4 Effervescent tablets 6 Not detected 5.5 Effervescent tablets 8 92.2 4.4 Effervescent tablets 9 92.1 4.2 Effervescent tablets 10 92.4 4.2 Effervescent tablets 11 79.8 4.5 Effervescent tablets 12 90.3 4.6 Dihydroquercetin water-soluble sample 76.0 /

[0042] (3) The present invention uses sodium hyaluronate as an auxiliary material for the dihydroquercetin effervescent tablet, which has a better solubilization effect under the condition of heating the acidic solution, changes the easy degradation property of sodium hyaluronate under the condition of heating the acidic aqueous solution, and improves the stability of the dihydroquercetin effervescent tablet.

[0043] "Study on the Extraction and Molecular Modification of Dihydroquercetin from Larix" (South China University of Technology, 2008) points out that the solubility of dihydroquercetin in water increases with the increase of temperature. "Study on the Extraction and Performance of Dihydroquercetin from Larix" (Harbin Normal University, 2012) points out that dihydroquercetin is thermally degraded with the increase of heating time at 100°C, and the color of the solution becomes darker visibly. Since the content detection of dihydroquercetin is related to solubility, it can be seen that the reduction of dihydroquercetin detected in the dihydroquercetin aqueous solution under heating conditions = thermal degradation part - heating solubilization part, among which the thermal degradation effect of dihydroquercetin is much greater than the heating solubilization effect, and it further decreases with the extension of heating time. The experimental results showed that the amount of dihydroquercetin in the water-soluble sample was reduced by 12.3% after being heated at 100°C for 30 minutes.

[0044] Under the condition of heating of acidic aqueous solution, the reduction of dihydroquercetin corresponding to effervescent tablets 1 to 5 prepared by the patent of the present invention using sodium hyaluronate as a solubilizer for dihydroquercetin is 4% to 5%. The sodium hyaluronate tasteless control of effervescent tablet 11 shows that the reduction of dihydroquercetin is 10.4% without adding sodium hyaluronate. According to the background technology, sodium hyaluronate will decompose under the condition of heating of acidic aqueous solution. It can be inferred that the solubility of effervescent tablets 1 to 5 aqueous solutions decreases under heating conditions, and the reduction of dihydroquercetin = heat-sensitive degradation part - heating solubilization part + sodium hyaluronate degradation causing dihydroquercetin dissolution reduction part. However, the test results of the present invention show that the reduction of dihydroquercetin in effervescent tablets 1 to 5 is less than that in effervescent tablet 11. It can be seen that sodium hyaluronate has an unexpected effect in the formulation, better stability, better corresponding solubilization effect, and the solubilization effect will be more significant as the heating time is prolonged.

[0045] Effervescent tablets 8 to 10 are the lactose-substituted control groups corresponding to Example 2, and the corresponding reduction in dihydroquercetin is similar to that of effervescent tablet 2. Lactose, as an auxiliary material, has little effect on the stability of sodium hyaluronate.

[0046] Effervescent tablet 12 is xanthan gum instead of sodium hyaluronate, and the corresponding reduction in dihydroquercetin is similar to that of effervescent tablet 11. The prior art shows that xanthan gum has good acid-base stability and thermal stability, so the solubilized part is stable in the effervescent tablet system. The test results show that the reduction in dihydroquercetin = the content of the heat-sensitive degradation part - the content of the heating solubilization part, which is similar to Example 11.

[0047] The dihydroquercetin content in effervescent tablet 6 was not detected for the reasons described in (2).

[0048] Combining effervescent tablets 1 to 5 and 8 to 10 to prepare effervescent tablets can increase the stability of sodium hyaluronate under the condition of heating an acidic solution, change the easy degradation property of sodium hyaluronate under the condition of heating an acidic aqueous solution, and at the same time improve the stability of dihydroquercetin effervescent tablets.

[0049] Table 3 Reduction of dihydroquercetin in the thermal stability experiment of effervescent tablets

[0050] Group Dihydroquercetin reduction (%) Group Dihydroquercetin reduction (%) Effervescent tablet 1 4.4 Effervescent tablets 8 4.4 Effervescent tablets 2 4.3 Effervescent tablets 9 4.4 Effervescent tablets 3 4.8 Effervescent tablets 10 4.0 Effervescent tablets 4 4.1 Effervescent tablets 11 10.4 Effervescent tablets 5 4.1 Effervescent tablets 12 11.2 Effervescent tablets 6 / Dihydroquercetin water-soluble sample 12.3 BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Figure 1 Liquid phase detection results of dihydroquercetin water-soluble samples, where the retention time of dihydroquercetin was 10.031min.

[0052] Figure 2 Liquid phase detection results of dihydroquercetin in the aqueous solution of effervescent tablet 2, wherein the retention time of dihydroquercetin is 10.028min. DETAILED DESCRIPTION

[0053] The following is further described in conjunction with specific examples. It should be noted that the following embodiments are provided to help understand the present invention, but do not constitute a limitation of the present invention.

[0054] Example 1: Preparation of dihydroquercetin composite effervescent tablet 1

[0055] 1. Formula

[0056] The formula in Table 4 is used to prepare 25 tablets of dihydroquercetin composite effervescent tablets 1 with an average tablet weight of 4 g / tablet. The content of each component in the composite vitamin and the content of the composite mineral component meet the national standard GB14880-2012. Among them, the composite minerals include 62.2% ferrous pyrophosphate content and 37.8% ferrous citrate content. The composite vitamin contains vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin D3, vitamin E, niacin, pantothenic acid, folic acid, and also contains fillers, which can be maltodextrin, starch, etc.

[0057] Table 4 Dihydroquercetin composite effervescent tablet formula 1

[0058] Recipe composition Mass (g / 100g effervescent tablet) Recipe composition Mass (g / 100g effervescent tablet) Dihydroquercetin 0.1 Citric Acid 28 Sodium Hyaluronate 0.6 Erythritol 26.8 Multivitamins 0.3 Stevia 0.5 Complex minerals 0.1 lactose 30 Sodium bicarbonate 11.8 essence 1.8

[0059] Table 5 Vitamin content in multivitamins

[0060] Ingredient Category Content (wt%) Ingredient Category Content (wt%) Vitamin C 34.7 Vitamin B6 0.4 Vitamin D3 0.1 Vitamin B12 0.01 Vitamin E 5.6 niacin 4.8 Vitamin B1 0.4 Pantothenic acid 1.3 Vitamin B2 1.7 Folic acid 0.9

[0061] 2. Preparation method

[0062] (1) Weighing raw materials other than lactose according to the formula, mixing, and crushing through a 100-mesh sieve;

[0063] (2) weighing 30-40 mesh lactose according to the formula, and adding it and the raw materials in step (1) into a mixer in equal amounts in multiple times, and mixing until the material has a uniform color and texture;

[0064] (3) Use a tablet press to compress the tablets and check the tablet weight differences.

[0065] Example 2: Preparation of dihydroquercetin composite effervescent tablet 2

[0066] Take the formula in Table 6 and adopt the preparation process in Example 1 to prepare 25 tablets of dihydroquercetin composite effervescent tablets 2 with an average tablet weight of 4 g / tablet. The specific composition ratio of the composite vitamins and composite minerals is as shown in Example 1.

[0067] Table 6 Dihydroquercetin composite effervescent tablet formula 2

[0068] Recipe composition Mass (g / 100g effervescent tablet) Recipe composition Mass (g / 100g effervescent tablet) Dihydroquercetin 0.2 Citric Acid 28 Sodium Hyaluronate 0.4 Sorbitol 24 Multivitamins 0.45 Sucralose 0.6 Complex minerals 0.05 lactose 27 Sodium bicarbonate 18 essence 1.3

[0069] Example 3: Preparation of dihydroquercetin composite effervescent tablet 3

[0070] Take the formula in Table 7 and adopt the preparation process in Example 1 to prepare 25 dihydroquercetin composite effervescent tablets with an average tablet weight of 4 g / tablet. The specific composition ratio of the composite vitamins and composite minerals is as shown in Example 1.

[0071] Table 7 Dihydroquercetin composite effervescent tablet formula 3

[0072] Recipe composition Mass (g / 100g effervescent tablet) Recipe composition Mass (g / 100g effervescent tablet) Dihydroquercetin 0.1 Citric Acid 37 Sodium Hyaluronate 0.2 Mannitol 18.18 Multivitamins 1.5 Saccharin Sodium 1.0 Complex minerals 0.02 lactose 16 Sodium bicarbonate 25 essence 1

[0073] Example 4: Preparation of dihydroquercetin composite effervescent tablet 4

[0074] On the basis of Example 3, tartaric acid was used to replace citric acid, and the specific formula was shown in Table 8. The preparation process of Example 1 was used to obtain a composite effervescent tablet 4. The specific composition ratio of the composite vitamins and composite minerals was as shown in Example 1.

[0075] Table 8 Dihydroquercetin composite effervescent tablet formula 4

[0076] Recipe composition Mass (g / 100g effervescent tablet) Recipe composition Mass (g / 100g effervescent tablet) Dihydroquercetin 0.1 tartaric acid 35 Sodium Hyaluronate 0.2 Sorbitol 18.38 Multivitamins 1.5 Acesulfame K 0.8 Complex minerals 0.02 lactose 19 Sodium bicarbonate 24 essence 1

[0077] Example 5: Preparation of dihydroquercetin composite effervescent tablet 5

[0078] On the basis of Example 1, malic acid was used to replace citric acid, and the specific formula was shown in Table 9. The preparation process of Example 1 was used to obtain a composite effervescent tablet 5. The specific composition ratio of the composite vitamins and composite minerals was as shown in Example 1.

[0079] Table 9 Dihydroquercetin effervescent tablet formula 5

[0080] Recipe composition Mass (g / 100g effervescent tablet) Recipe composition Mass (g / 100g effervescent tablet) Dihydroquercetin 0.1 Malic Acid 27 Sodium Hyaluronate 0.6 Sorbitol 26.8 Multivitamins 0.3 Sucralose 0.5 Complex minerals 0.1 lactose 30 Sodium bicarbonate 12.8 essence 1.8

[0081] Example 6: Preparation of dihydroquercetin composite effervescent tablet 6

[0082] Take the formula in Table 10 and adopt the preparation process of Example 1 to obtain 25 tablets of dihydroquercetin composite effervescent tablets 6 with an average tablet weight of 4 g / tablet. The specific composition ratio of the composite vitamins and composite minerals is as shown in Example 1.

[0083] Table 10 Dihydroquercetin effervescent tablet formula 6

[0084]

[0085]

[0086] Example 7: Preparation of dihydroquercetin composite effervescent tablet 7

[0087] Take the formula in Table 11 and adopt the preparation process in Example 1 to obtain 25 tablets of dihydroquercetin composite effervescent tablets 7 with an average tablet weight of 4 g / tablet. The specific composition ratio of the composite vitamins and composite minerals is as shown in Example 1.

[0088] Table 11 Dihydroquercetin composite effervescent tablet formula 7

[0089] Recipe composition Mass (g / 100g effervescent tablet) Recipe composition Mass (g / 100g effervescent tablet) Dihydroquercetin 0.2 Citric Acid 28 Sodium Hyaluronate 0.3 starch 28 Multivitamins 0.2 Sucralose 0.5 Complex minerals 0.2 lactose 23.6 Sodium bicarbonate 18 essence 1

[0090] Example 8: Preparation of dihydroquercetin composite effervescent tablet 8

[0091] On the basis of Example 2, lactose was removed, sorbitol was added and the ratio of sodium bicarbonate to citric acid was adjusted, and the preparation process of Example 1 was adopted to obtain a composite effervescent tablet 8. The specific formula is shown in Table 12.

[0092] Table 12 Dihydroquercetin composite effervescent tablet formula 8

[0093] Recipe composition Mass (g / 100g effervescent tablet) Recipe composition Mass (g / 100g effervescent tablet) Dihydroquercetin 0.2 Citric Acid 40 Sodium Hyaluronate 0.4 Sorbitol 28.2 Multivitamins 0.45 Sucralose 0.9 Complex minerals 0.05 lactose 0 Sodium bicarbonate 28 essence 1.8

[0094] Example 9: Preparation of dihydroquercetin composite effervescent tablets 9-10

[0095] On the basis of Example 2, glucose was used to replace lactose to obtain composite effervescent tablet 9; mannose was used to replace lactose to obtain composite effervescent tablet 10. Composite effervescent tablets 9-10 were prepared by using the preparation process of Example 1 and making appropriate adjustments according to the formula.

[0096] Example 10: Preparation of dihydroquercetin composite effervescent tablets 11-12

[0097] On the basis of Example 2, sodium hyaluronate was removed and the lactose content was increased to prepare a composite effervescent tablet 11; on the basis of Example 2, xanthan gum was used to replace sodium hyaluronate to prepare an effervescent tablet 12. Composite effervescent tablets 11-12 were obtained by optimizing the preparation process of Example 1.

[0098] Example 11: General Quality Inspection of Effervescent Tablets

[0099] 1. Test content

[0100] 1.1 Hardness test

[0101] Take 3 effervescent tablets of each of Examples 1 to 12, and check the hardness of the effervescent tablets with a tablet four-purpose tester, which should comply with the provisions of the 2020 edition of the "Chinese Pharmacopoeia".

[0102] 1.2 Disintegration test of composite effervescent tablets

[0103] Take 6 effervescent tablets of Examples 1 to 12, place them in a beaker filled with 200 mL warm water (about 20°C), and when the gas around the tablets stops escaping, the tablets should dissolve completely without residue. Effervescent tablets should disintegrate within 5 minutes. If the disintegration exceeds 5 minutes, it will not meet the qualified standard.

[0104] 1.3 pH determination

[0105] Take 2 effervescent tablets of Examples 1 to 12, respectively, and disperse them in 100 mL of 20° C. distilled water. Measure the pH value of each solution, and calculate the average value of the results three times.

[0106] 2. Test results

[0107] Table 13 Test results of hardness, disintegration time and pH value of dihydroquercetin composite effervescent tablets

[0108] sample Hardness(N) Disintegration time (min) pH Effervescent tablet 1 44 3.0 4.7 Effervescent tablets 2 46 2.8 4.3 Effervescent tablets 3 40 3.1 4.5 Effervescent tablets 4 46 2.4 4.3 Effervescent tablets 5 42 2.4 4.4 Effervescent tablets 6 55 6.4 5.5 Effervescent tablets 7 Cannot be formed / / Effervescent tablets 8 40 7.8 4.4 Effervescent tablets 9 26 5.6 4.2 Effervescent tablets 10 36 4.2 4.2 Effervescent tablets 11 44 2.5 4.5 Effervescent tablets 12 42 2.4 4.6

[0109] The disintegration time of effervescent tablets 1 to 5 is less than 3.1 min; after removing lactose from effervescent tablet 2, the sorbitol content is increased and the ratio of sodium bicarbonate to citric acid is adjusted to obtain effervescent tablet 8, which has a disintegration time of 7.8 min, which is more than 2.5 times the disintegration time of effervescent tablets 1 to 5. After replacing the lactose in effervescent tablet 2 with glucose and mannose, effervescent tablets 9 and 10 are obtained, respectively, with disintegration times of 5.6 min and 4.2 min, which are 1.5 to 2 times the disintegration time of effervescent tablet 2. It can be seen that lactose has a better disintegration effect than similar sugars.

[0110] Effervescent tablets 6 and 7 were prepared using a formulation outside the scope of the present invention, wherein the disintegration time of effervescent tablet 6 was 6.4 min, which was more than twice the disintegration time of the effervescent tablet within the scope of the present invention, and effervescent tablet 7 could not be formed. The reason is that when the effervescent tablet is prepared by direct powder compression, high requirements are placed on mixing uniformity, compressibility of auxiliary materials, fluidity, etc., and the use of unreasonable types or contents of auxiliary materials has a great influence on the tablet forming, disintegration, etc.

[0111] Effervescent tablet 11 is obtained by removing sodium hyaluronate from effervescent tablet 2, and effervescent tablet 12 is obtained by replacing sodium hyaluronate in effervescent tablet 2 with xanthan gum. The corresponding disintegration times of the two are not much different from those of effervescent tablet 2, and are both better than effervescent tablets 6 to 10. The reason is that sodium hyaluronate accounts for a small proportion in the effervescent tablet and has little effect on lactose-promoted disintegration.

[0112] The effervescent tablets 1-5, 11-12 protected by the present invention use lactose as an auxiliary material, and have specificity in the selection of the types and contents of the corresponding formulation ingredients. Without adding lubricants and disintegrants, the technical problem of poor disintegration in the direct compression preparation process of the effervescent tablets can be better solved.

[0113] Example 12: Comparison of dihydroquercetin transfer rate

[0114] 1. Experimental process

[0115] 1.1 Preparation of dihydroquercetin reference solution

[0116] Accurately weigh 13.38 mg of dihydroquercetin and dissolve it in methanol to make up to 100 mL. Take an appropriate amount and filter it through a 0.22 μm filter membrane, and take the filtrate for liquid phase detection.

[0117] 1.2 Dihydroquercetin water-soluble sample

[0118] Accurately weigh 20.39 mg of dihydroquercetin, dissolve it in 1000 mL of water, take an appropriate amount and pass it through a 0.22 μm filter membrane, and take the filtrate for liquid phase detection.

[0119] 1.3 Preparation of effervescent tablet samples

[0120] Take one effervescent tablet and dissolve it in 50 mL of water. Take an appropriate amount and filter it through a 0.22 μm filter membrane. Take the filtrate for liquid phase detection.

[0121] 1.4 Liquid phase conditions

[0122] Agilent ZORBAX XDB-C18 (4.6*250nm, 5μm) chromatographic column, mobile phase program as shown in Table 14, flow rate: 1mL / min; column temperature: 30℃; wavelength: 288nm; injection volume: 10μL.

[0123] Table 14 Mobile phase program

[0124]

[0125] 1.5 Calculation of dihydroquercetin dissolution transfer rate

[0126] Dissolution transfer rate = dihydroquercetin content after dissolution / theoretical value of dihydroquercetin content*100%.

[0127] 2. Test results

[0128] Table 15 Dihydroquercetin composite effervescent tablet dissolution transfer rate results

[0129] Group Dissolution transfer rate (%) Group Dissolution transfer rate (%) Effervescent tablet 1 92.5 Effervescent tablets 8 92.2 Effervescent tablets 2 91.5 Effervescent tablets 9 92.1 Effervescent tablets 3 90.2 Effervescent tablets 10 92.4 Effervescent tablets 4 91.1 Effervescent tablets 11 79.8 Effervescent tablets 5 92.0 Effervescent tablets 12 90.3 Effervescent tablets 6 Not detected Dihydroquercetin water-soluble sample 76.0

[0130] The liquid phase spectra of dihydroquercetin water-soluble sample and effervescent tablet 2 are as follows Figure 1 and Figure 2 As shown, the pH value of the dihydroquercetin water-soluble sample is 6.35. The test results show that the dissolution transfer rate of dihydroquercetin in effervescent tablets 1 to 5, effervescent tablets 8 to 10, and effervescent tablet 12 is greater than 90%, which is significantly better than that of effervescent tablet 11 and the dihydroquercetin water-soluble sample.

[0131] The inventor of this patent found in the research process that the dissolution transfer rate of dihydroquercetin in the dihydroquercetin water-soluble sample is only 76%, and the dissolution transfer rate = dihydroquercetin content after dissolution / theoretical value of dihydroquercetin content*100%. The higher the dissolution transfer rate, the better the solubility. Literature search found that the solubility of dihydroquercetin in water is less than 2g / 100g solvent. Because dihydroquercetin effervescent tablets need to be taken with water during administration, increasing the dissolution transfer rate of dihydroquercetin can better exert the antioxidant effect of the product.

[0132] The dissolution transfer rate of the effervescent tablets 1 to 5 prepared by using sodium hyaluronate as a solubilizer for dihydroquercetin is 90% to 92.5%, which is much higher than the dissolution transfer rate of the water-soluble dihydroquercetin sample of 76%. Effervescent tablets 8 to 10 are the lactose-substituted control group corresponding to Example 2, and the corresponding dissolution transfer rate is about 92%, which shows that the excipient lactose has little effect on the dissolution transfer rate of dihydroquercetin.

[0133] Effervescent tablet 6 is a formulation outside the scope of protection of the present invention, and its dihydroquercetin dissolution transfer rate is not detected. Through prior art search and analysis, it is found that the characteristic absorption peak of dihydroquercetin does not change substantially under acidic conditions, but as the pH value increases, the characteristic peak absorption wavelength increases significantly, and dihydroquercetin may be degraded. The pH value of effervescent tablet 6 after dissolution is 5.5, and dihydroquercetin is not detected due to the displacement of the characteristic peak. It can be seen from the above that the formulation of effervescent tablet 6 cannot promote the improvement of dissolution transfer rate under the premise of ensuring the antioxidant effect of dihydroquercetin.

[0134] The present invention also provides a sodium hyaluronate tasteless control effervescent tablet 11 of the effervescent tablet 2, and an effervescent tablet 12 in which sodium hyaluronate is replaced by xanthan gum. The dissolution transfer rate comparison shows that the dissolution transfer rate of the effervescent tablet 11 is similar to that of the dihydroquercetin water-soluble sample, which shows that sodium hyaluronate in the dihydroquercetin effervescent tablet of the present invention is the main component that promotes the dissolution of dihydroquercetin. The dissolution transfer rate of the effervescent tablet 12 is similar to that of the effervescent tablet 2, which shows that both sodium hyaluronate and xanthan gum have the effect of promoting the dissolution of dihydroquercetin.

[0135] The effervescent tablets 1 to 5, 8 to 10 and 12 protected by the present invention use sodium hyaluronate and xanthan gum to increase the dissolution transfer rate of dihydroquercetin, which can be better absorbed by the human body and exert the antioxidant effect of the product.

[0136] Example 13: Comparison of thermal stability of effervescent tablets

[0137] 1. Test methods

[0138] 1.1 Dihydroquercetin aqueous solution water bath sample

[0139] Accurately weigh 10.19 mg of dihydroquercetin, dissolve in 100 mL of water, and dissolve by ultrasonication. Heat the dihydroquercetin solution in a water bath at 100° C. for 30 min. Take an appropriate amount and filter through a 0.22 μm filter membrane, take the filtrate, and determine the dihydroquercetin content according to the liquid phase conditions of Example 12.

[0140] 1.2 Water bath sample of composite effervescent tablet aqueous solution

[0141] Take 1 effervescent tablet of samples 1-6 and 8-12, dissolve it in 50 mL of water, heat it in a water bath at 100° C. for 30 min, take an appropriate amount and filter it through a 0.22 μm filter membrane, take the filtrate, and determine the dihydroquercetin content according to the liquid phase conditions of Example 12.

[0142] 1.3 Determination of dihydroquercetin content before heating

[0143] The liquid phase detection conditions of Example 12 were used to detect the dihydroquercetin content in the dihydroquercetin aqueous solution sample and the composite effervescent tablet dissolved sample before water bathing.

[0144] 1.4 Calculation of dihydroquercetin reduction

[0145] Dihydroquercetin reduction amount = (sample concentration after water bath - sample concentration before water bath) / sample concentration before water bath * 100%.

[0146] 2. Test results

[0147] Table 16 Dihydroquercetin composite effervescent tablet thermal stability test results

[0148] Group Dihydroquercetin reduction (%) Group Dihydroquercetin reduction (%) Effervescent tablet 1 4.4 Effervescent tablets 8 4.4 Effervescent tablets 2 4.3 Effervescent tablets 9 4.4 Effervescent tablets 3 4.8 Effervescent tablets 10 4.0 Effervescent tablets 4 4.1 Effervescent tablets 11 10.4 Effervescent tablets 5 4.1 Effervescent tablets 12 11.2 Effervescent tablets 6 Not detected Dihydroquercetin water-soluble sample 12.3

[0149] The test results are shown in Table 16. The reduction in dihydroquercetin corresponding to effervescent tablets 1 to 5 and effervescent tablets 8 to 10 is similar, and is significantly less than that of effervescent tablets 11, 12 and the dihydroquercetin water-soluble sample.

[0150] "Study on the Extraction and Molecular Modification of Dihydroquercetin from Larix" (South China University of Technology, 2008) points out that the solubility of dihydroquercetin in water increases with the increase of temperature. "Study on the Extraction and Performance of Dihydroquercetin from Larix" (Harbin Normal University, 2012) points out that dihydroquercetin is thermally degraded with the increase of heating time at 100°C, and the degradation effect becomes more obvious with the extension of heating time, and the color of the solution becomes darker with the naked eye. Since the content detection of dihydroquercetin is related to solubility, it can be seen that the reduction of dihydroquercetin detected in the dihydroquercetin aqueous solution under heating conditions = thermal degradation part - heating solubilization part, among which the thermal degradation effect of dihydroquercetin is much greater than the heating solubilization effect, and it further decreases with the extension of heating time. The experimental results showed that the amount of dihydroquercetin in the water-soluble sample was reduced by 12.3% after being heated at 100°C for 30 minutes.

[0151] Under the condition of heating of acidic aqueous solution, the dihydroquercetin reduction amount of effervescent tablets 1 to 5 prepared by using sodium hyaluronate as a solubilizer for dihydroquercetin is 4% to 5%. The sodium hyaluronate tasteless control of effervescent tablet 11 shows that the reduction amount of dihydroquercetin is 10.4% without adding sodium hyaluronate. According to the background technology, sodium hyaluronate will decompose under the condition of heating of acidic aqueous solution. It can be inferred that the solubility of effervescent tablets 1 to 5 aqueous solutions decreases under heating conditions, and the reduction amount of dihydroquercetin = heat-sensitive degradation part - heating solubilization part + sodium hyaluronate degradation causing dihydroquercetin dissolution reduction part. However, the test results show that the reduction amount of dihydroquercetin in effervescent tablets 1 to 5 is less than that in effervescent tablet 11, which shows that sodium hyaluronate has an unexpected effect in the formulation, better stability, better corresponding solubilization effect, and the solubilization effect will be more significant as the heating time is prolonged.

[0152] Effervescent tablets 8 to 10 are the lactose-substituted control groups corresponding to Example 2, and the corresponding reduction in dihydroquercetin is similar to that of effervescent tablet 2. Lactose, as an auxiliary material, has little effect on the stability of sodium hyaluronate.

[0153] Effervescent tablet 12 is xanthan gum instead of sodium hyaluronate, and the corresponding reduction in dihydroquercetin is similar to that of effervescent tablet 11. The prior art shows that xanthan gum has good acid-base stability and thermal stability, so the solubilized part is stable in the effervescent tablet system. The test results show that the reduction in dihydroquercetin = the content of the heat-sensitive degradation part - the content of the heating solubilization part, which is similar to Example 11.

[0154] The dihydroquercetin content in effervescent tablet 6 was not detected for the reasons described in Example 12.

[0155] Combining effervescent tablets 1 to 5 and 8 to 10 to prepare effervescent tablets can increase the stability of sodium hyaluronate under the condition of heating an acidic solution, change the easy degradation property of sodium hyaluronate under the condition of heating an acidic aqueous solution, and at the same time improve the stability of dihydroquercetin effervescent tablets.

Claims

1. A dihydroquercetin composite effervescent tablet, characterized in that: The effervescent tablet is composed of the following components and their mass percentages: dihydroquercetin 0.1%-0.3%, stabilizer 0.2%-0.6%, complex vitamins 0.3%-1.5%, complex minerals 0.02%-0.1%, filler 15%-30%, sweetener 0.5%-1%, lactose 0-30%, alkali source 10%-30%, acid source 25%-40%, essence 1%-2%, the sum of the mass percentages of the components is 1, the stabilizer is sodium hyaluronate or xanthan gum, The compound vitamins include one or more of vitamin C, vitamin D, vitamin E, vitamin B1, vitamin B2, vitamin B12, niacin, folic acid, and pantothenic acid. The composite minerals include iron ions and zinc ions, wherein the iron ions include one or two of ferrous gluconate and ferrous fumarate, and the zinc ions include one or more of glycyrrhizic zinc, zinc citrate, and zinc gluconate; The filler includes one or more of erythritol, sorbitol and mannitol.

2. The dihydroquercetin composite effervescent tablet according to claim 1, characterized in that The lactose may be replaced by glucose or mannitol.

3. The dihydroquercetin composite effervescent tablet according to claim 1 or 2, characterized in that, The stabilizer is sodium hyaluronate.

4. The dihydroquercetin composite effervescent tablet according to claim 1, characterized in that The mass percentage of lactose is 15%-30%.

5. The dihydroquercetin composite effervescent tablet according to claim 1 or 2, characterized in that: The content of each vitamin component in the complex vitamin and the content of each mineral component in the complex mineral meet the national standards for the use of food nutrient enhancers.

6. The dihydroquercetin composite effervescent tablet according to claim 1 or 2, characterized in that: The sweetener is one or more of sucralose, saccharin sodium, acesulfame potassium or stevioside.

7. The dihydroquercetin composite effervescent tablet according to claim 1 or 2, characterized in that: The alkali source is sodium bicarbonate, and the acid source is one or more of citric acid, tartaric acid or malic acid.

8. The dihydroquercetin composite effervescent tablet according to claim 1 or 2, characterized in that: The mass ratio of the alkali source to the acid source is 0.4:1-0.7:

1.

9. A method for preparing the dihydroquercetin composite effervescent tablet according to claim 1 or 2, characterized in that: The preparation method comprises the following steps: (1) weighing the raw materials except lactose according to the formula, mixing, and crushing through a 80-100 mesh sieve; (2) weighing 30-40 mesh lactose according to the formula, and adding it and the raw materials in step (1) into a mixer in equal amounts in multiple times, and mixing until the material has a uniform color and texture; (3) Tablets were compressed using a tablet press and the weight difference of the tablets was checked. The hardness of the obtained tablets was 36N-46N.

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