Composite probiotic chewable tablet and production method thereof

Abstract

The invention relates to the technical field of chewable tablets, and discloses a composite probiotic chewable tablet and a production method thereof, the probiotic chewable tablet comprises the following raw materials: probiotic powder, puerarin-loaded sustained release microspheres, erythritol, isomaltooligosacharide, lemon powder and magnesium stearate; wherein the puerarin-loaded sustained-release microspheres are formed by embedding puerarin through a complex coacervation method, shell layers of the puerarin-loaded sustained-release microspheres are protamine and modified sodium polymannuronate, and after the puerarin-loaded sustained-release microspheres reach the intestinal tract, the intestinal tract adhesion can be realized to achieve the purpose of targeted drug delivery, so that the puerarin can be continuously and slowly released in the intestinal tract; the chewable tablet effectively improves the treatment effect of the chewable tablet on diarrhea, reduces adverse reactions, shortens the cure time, reduces side effects, ensures the safety and reliability of the product, and has a wide market prospect.

Description

Technical Field

[0001] The present invention relates to the technical field of chewable tablets, and in particular to a composite probiotic chewable tablet and a production method thereof. Background Art

[0002] Chewable tablets are tablets that can be chewed and swallowed in the mouth. They have the advantages of good taste, portability, and a long shelf life. Chewing promotes the dissolution and absorption of nutrients in the tablet. Due to the accelerated pace of life, increased work pressure, and unhealthy lifestyle habits in modern society, such as irregular diet and sleep, the ecological balance of the intestines has been severely disrupted, leading to frequent intestinal health problems such as constipation and diarrhea. Diarrhea is a common symptom of digestive system diseases. It refers to an increase in the frequency of bowel movements or a change in the shape of the stool, such as thin stools, increased water content, undigested food, pus, blood, or mucus. It may also be accompanied by symptoms such as fever, mental fatigue, and weight loss.

[0003] The mechanisms of diarrhea often vary depending on the cause. During intestinal infection, the intestines are stimulated by pathogenic microorganisms and their toxins, increasing the secretion of chemical inflammatory mediators, accelerating intestinal motility and shortening the residence time of nutrients in the intestine. Nutrients are not fully absorbed and are excreted from the body, causing diarrhea. This, combined with the disruption of the normal ecological balance of intestinal flora and the resulting dysbiosis, has gradually become a research focus. As humans increasingly value intestinal health, probiotics have begun to be introduced into human life to regulate intestinal health. Probiotics are a type of active microorganism that can improve the balance of the host's intestinal microecology and impart various health functions to the host. By regulating the balance of intestinal flora, they inhibit the growth of pathogenic bacteria and enhance the body's defenses, thereby effectively improving gastrointestinal dysfunction and alleviating symptoms such as diarrhea and constipation. However, chewable tablets currently used to treat diarrhea suffer from a short duration of action and require frequent or high-dose administration.

[0004] The invention patent with publication number CN112057479B discloses a probiotic composition that can relieve diarrhea caused by antibiotics. The probiotic composition is made from composite probiotics, Radix Trichosanthis, and bitter melon seed extract as the main raw materials. It is a safe, high-quality, effective, and low-cost probiotic composition that can relieve diarrhea caused by antibiotics. By adding Radix Trichosanthis and bitter melon seed extract, it can synergistically promote the production of bacteriocins, a metabolite of Lactobacillus rhamnosus, slow the growth of intestinal pathogens, purify the intestinal environment, adjust intestinal flora imbalance, reduce intestinal inflammation levels, and promote the recovery of gastrointestinal function. Therefore, the therapeutic effect of chewable tablets on diarrhea can be improved by optimizing the basic materials. Summary of the Invention

[0005] In order to solve the problems mentioned in the background technology, the purpose of the present invention is to provide a composite probiotic chewable tablet and a production method thereof.

[0006] The purpose of the present invention can be achieved through the following technical solutions: A method for producing a composite probiotic chewable tablet, the probiotic chewable tablet comprising the following raw materials in parts by weight: 30-50 parts of probiotic powder, 4-8 parts of puerarin-loaded sustained-release microspheres, 15-25 parts of erythritol, 10-20 parts of isomaltooligosaccharide, 10-15 parts of lemon powder, and 1-2 parts of magnesium stearate; The production method comprises the following steps: (1) Erythritol, oligomaltodextrose and lemon powder were added to a grinder for grinding and sieving respectively. The ground materials were added to a mixer and stirred for 25 to 35 minutes. Puerarin sustained-release microspheres were then added and mixed evenly. Deionized water was then slowly added. Under the action of continuous stirring, the materials were gradually moistened. The materials were then kneaded into a mass and dispersed to obtain a soft material. (2) The obtained soft material is placed in a swing granulator for granulation. After granulation, it is placed in a blast drying oven at 55-65°C for drying. The dried granules are sieved through a 12-16 mesh sieve to obtain dry granules. (3) Magnesium stearate and probiotic powder are added to the dry granules, mixed evenly, and then compressed using a single punch tablet press to prepare probiotic chewable tablets.

[0007] Furthermore, in step (1), the mesh size of the sieving is 80 to 120 meshes.

[0008] Furthermore, in step (2), the drying end point is a particle moisture content of 1 to 4%.

[0009] Furthermore, in step (3), the probiotic powder is Bifidobacterium lactis and Lactobacillus rhamnosus, with a mass ratio of 3:1.

[0010] Furthermore, the preparation method of the puerarin-loaded sustained-release microspheres comprises the following steps: A1: Mix protamine with deionized water and disperse them by ultrasonication for 40-50 minutes to prepare a protamine solution; mix modified sodium polymannuronate with deionized water and disperse them by ultrasonication for 30-40 minutes to prepare a modified sodium polymannuronate solution; A2: Add puerarin to the protamine solution and mix well. Then add the modified sodium polymannuronate solution and emulsify at 900-1100 r / min for 3-5 minutes using a high-speed disperser. Then stir at 35-45°C and 300-500 r / min for 20-40 minutes. Cool to 8-12°C, adjust the pH value of the system to neutral with sodium hydroxide solution, add a curing agent, cure for 5-7 hours, let stand, filter, and freeze-dry to obtain puerarin-loaded sustained-release microspheres.

[0011] Furthermore, in step A2, the mass fraction of the sodium hydroxide solution is 10% to 50%.

[0012] Furthermore, in step A2, the curing agent is transglutaminase.

[0013] Furthermore, the preparation method of the modified sodium polymannuronate solution comprises the following steps: Sodium polymannuronate is added to deionized water, mechanically stirred evenly, cysteine ​​and N,N'-dicyclohexylcarbodiimide are added, the temperature is raised to 90-110°C under stirring, kept warm for 5-7 hours, cooled and discharged, and the modified sodium polymannuronate can be obtained.

[0014] Furthermore, the mass ratio of the sodium polymannuronate to cysteine ​​is 1:0.1-0.3.

[0015] A composite probiotic chewable tablet is prepared by the above production method.

[0016] Beneficial effects of the present invention: (1) The probiotic chewable tablets prepared by the present invention can be used to treat diarrhea. By properly combining raw materials and auxiliary materials such as probiotic powder, puerarin-loaded sustained-release microspheres, and erythritol, synergistic enhancement between the ingredients is achieved, which can effectively improve the effect of treating diarrhea, reduce adverse reactions, and shorten the recovery time. At the same time, the occurrence of side effects is reduced, thereby ensuring the safety and reliability of the product and having broad market prospects.

[0017] (2) The present invention prepares a puerarin-loaded sustained-release microsphere with a shell of protamine and modified sodium polymannuronate and a core of puerarin. Since puerarin has poor stability in gastrointestinal fluid and a short retention time, which affects its intestinal targeted delivery efficiency, the stability of puerarin in gastrointestinal fluid can be improved by coating with protamine and modified sodium polymannuronate. When puerarin acts on the intestine, it can relieve the inflammatory state during diarrhea, reduce the damage of inflammatory factors to the intestinal mucosa, inhibit small intestinal peristalsis and reduce gastric emptying rate, significantly reducing the frequency of diarrhea. At the same time, it can regulate the secretion of gastrointestinal hormones and make the intestinal function tend to normal, thereby achieving the effect of antidiarrheal. When the puerarin-loaded sustained-release microspheres reach the intestine, the thiol groups in the shell structure can form disulfide bonds with the thiol groups on the mucin in the intestinal mucus, thereby achieving intestinal adhesion and achieving the purpose of targeted drug delivery. Puerarin can be released continuously and slowly in the intestine, effectively improving the therapeutic effect of chewable tablets on diarrhea, avoiding the problems of short action time in the intestine and the need for frequent or large-dose administration. In addition, the shell structure has good antioxidant and antibacterial effects. On the one hand, it can remove oxygen free radicals in the intestine and reduce their damage to the biofilm, thereby inhibiting the increase in intestinal permeability. On the other hand, it can inhibit the reproduction of pathogenic bacteria in the intestine, thereby maintaining the balance of intestinal flora and improving intestinal health.

[0018] Of course, any product implementing the present invention does not necessarily need to achieve all of the advantages described above at the same time. DETAILED DESCRIPTION

[0019] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts shall fall within the scope of protection of the present invention.

[0020] Example 1 1. Preparation of modified sodium polymannuronate 6 g of sodium polymannuronate was added to deionized water, mechanically stirred, purged with nitrogen, and the air was expelled. Then, 1.2 g of cysteine ​​and 0.05 g of N,N'-dicyclohexylcarbodiimide were added. The system temperature was raised to 100°C while stirring, kept warm for 6 h, cooled and discharged to obtain modified sodium polymannuronate.

[0021] Elemental analysis: Sodium polymannuronate and modified sodium polymannuronate were placed in a CHN628 elemental analyzer for elemental content analysis. The tested element was mainly N. After testing, no nitrogen was detected in sodium polymannuronate, while the percentage of nitrogen in modified sodium polymannuronate was 4.1%. The nitrogen content increased, indicating that cysteine ​​was successfully introduced into the structure of sodium polymannuronate.

[0022] 2. Preparation of Puerarin-loaded Sustained-Release Microspheres A1: 5 g of protamine was mixed with 95 g of deionized water and ultrasonically dispersed for 45 min to prepare a protamine solution; 5 g of modified sodium polymannuronate was mixed with 95 g of deionized water and ultrasonically dispersed for 35 min to prepare a modified sodium polymannuronate solution; A2: Add 2.8 g of puerarin to the protamine solution, mix well, then add the modified sodium polymannuronate solution, use a high-speed disperser to emulsify at 1000 r / min for 4 minutes, then stir at 40°C and 400 r / min for 30 minutes, cool to 10°C, adjust the pH value of the system to neutral with 30% sodium hydroxide solution, add 1 g of glutamine transaminase, solidify for 6 hours, let stand, filter, and freeze-dry to obtain puerarin-loaded sustained-release microspheres.

[0023] 4 g of puerarin-loaded sustained-release microspheres were placed in 20 ml of anhydrous ethanol and their structure was destroyed by ultrasound to completely release the loaded puerarin into the solution. The absorbance of the solution at a wavelength of 288 nm was recorded using a UV / visible spectrophotometer. The puerarin content in the puerarin-loaded sustained-release microspheres was calculated, and the inclusion rate was calculated using the following formula: inclusion rate = (mass of puerarin in the sustained-release microspheres / total puerarin feed amount) × 100%. After calculation, the inclusion rate of the puerarin-loaded sustained-release microspheres was 75.3%.

[0024] Technical principle: In the modified sodium polymannuronate, cysteine ​​is introduced into the structure of sodium polymannuronate by chemical connection; in the puerarin-loaded sustained-release microspheres, puerarin is encapsulated by the complex coacervation method. First, protamine is positively charged in the solution, and the modified sodium polymannuronate is negatively charged in the solution. A tight shell structure is formed through the connection between the positive and negative charges, and the coacervate phase generated after charge neutralization will encapsulate the inner core puerarin. After the new phase is formed, it settles in the solution to form puerarin-loaded sustained-release microspheres.

[0025] 3. Preparation of Probiotic Chewable Tablets (1) 15g of erythritol, 10g of oligosaccharide and 10g of lemon powder were added to a grinder and ground respectively. The ground materials were passed through an 80-mesh sieve and added to a mixer. The mixture was stirred for 25 minutes. 4g of puerarin-loaded sustained-release microspheres were then added. After mixing evenly, deionized water was slowly added. Under continuous stirring, the materials were gradually moistened. The materials were then kneaded into a mass and dispersed to obtain a soft material. (2) The obtained soft material is placed in a swing granulator for granulation. After granulation, it is placed in a blast drying oven at 55°C for drying. The drying end point is when the moisture content of the granules is 1%. The dried granules are sieved through a 12-mesh sieve to obtain dry granules. (3) Add 1 g of magnesium stearate, 22.5 g of Bifidobacterium lactis and 7.5 g of Lactobacillus rhamnosus to the dry granules, mix well and press into tablets using a single punch tablet press to prepare probiotic chewable tablets.

[0026] Example 2 Preparation of probiotic chewable tablets (1) 20g of erythritol, 15g of oligosaccharide isomaltose and 12g of lemon powder were added to a grinder and ground respectively. After passing through a 100-mesh sieve, the ground materials were added to a mixer and stirred for 30min. Then, 6g of puerarin-loaded sustained-release microspheres were added. After mixing evenly, deionized water was slowly added. Under the action of continuous stirring, the materials were gradually moistened. Then, they were kneaded into a mass and dispersed to obtain a soft material. (2) The obtained soft material is placed in a swing granulator for granulation. After granulation, it is placed in a 60°C forced air drying oven for drying. The drying end point is when the moisture content of the granules is 3%. The dried granules are sieved through a 14-mesh sieve to obtain dry granules. (3) Add 1.5 g of magnesium stearate, 30 g of Bifidobacterium lactis and 10 g of Lactobacillus rhamnosus to the dry granules, mix well and press into tablets using a single punch tablet press to prepare probiotic chewable tablets.

[0027] The preparation method of puerarin-loaded sustained-release microspheres is the same as that in Example 1.

[0028] Example 3 Preparation of probiotic chewable tablets (1) 25g of erythritol, 20g of oligosaccharide and 15g of lemon powder were added to a grinder and ground respectively. After passing through a 120-mesh sieve, the ground materials were added to a mixer and stirred for 35 minutes. Then, 8g of puerarin-loaded sustained-release microspheres were added. After mixing evenly, deionized water was slowly added. Under the action of continuous stirring, the materials were gradually moistened. Then, they were kneaded into a mass and dispersed to obtain a soft material. (2) The obtained soft material is placed in a swing granulator for granulation. After granulation, it is placed in a 65°C forced air drying oven for drying. The drying end point is when the moisture content of the granules is 4%. The dried granules are sieved through a 16-mesh sieve to obtain dry granules. (3) Add 2 g of magnesium stearate, 37.5 g of Bifidobacterium lactis and 12.5 g of Lactobacillus rhamnosus to the dry granules, mix well and press into tablets using a single punch tablet press to prepare probiotic chewable tablets.

[0029] The preparation method of puerarin-loaded sustained-release microspheres is the same as that in Example 1.

[0030] Comparative Example 1 Preparation of probiotic chewable tablets (1) 20g of erythritol, 15g of oligosaccharide and 12g of lemon powder were added to a grinder and ground respectively. After passing through a 100-mesh sieve, the ground materials were added to a mixer and stirred for 30min. 2.5g of protamine, 2.5g of sodium polymannuronate and 1g of puerarin were added. After mixing evenly, deionized water was slowly added. Under the action of continuous stirring, the materials were gradually moistened. After kneading them into a mass, they could be dispersed to obtain a soft material. (2) The obtained soft material is placed in a swing granulator for granulation. After granulation, it is placed in a 60°C forced air drying oven for drying. The drying end point is when the moisture content of the granules is 3%. The dried granules are sieved through a 14-mesh sieve to obtain dry granules. (3) Add 1.5 g of magnesium stearate, 30 g of Bifidobacterium lactis and 10 g of Lactobacillus rhamnosus to the dry granules, mix well and press into tablets using a single punch tablet press to prepare probiotic chewable tablets.

[0031] Comparative Example 2 Preparation of probiotic chewable tablets (1) 20g of erythritol, 15g of oligosaccharide and 12g of lemon powder were added to a grinder and ground respectively. After passing through a 100-mesh sieve, the ground materials were added to a mixer and stirred for 30min. Deionized water was slowly added. Under the action of continuous stirring, the materials gradually became moist. Then, they were kneaded into a mass and dispersed to obtain a soft material. (2) The obtained soft material is placed in a swing granulator for granulation. After granulation, it is placed in a 60°C forced air drying oven for drying. The drying end point is when the moisture content of the granules is 3%. The dried granules are sieved through a 14-mesh sieve to obtain dry granules. (3) Add 1.5 g of magnesium stearate, 30 g of Bifidobacterium lactis and 10 g of Lactobacillus rhamnosus to the dry granules, mix well and press into tablets using a single punch tablet press to prepare probiotic chewable tablets.

[0032] Performance testing: 42 rats weighing 150±5g were randomly divided into 6 groups. Under anesthesia, each rat was gavaged with 1.5ml of 0.2g / ml senna solution to maintain the rat diarrhea state. After 1h, the probiotic chewable tablets prepared in Examples 1 to 3 and Comparative Examples 1 to 2 were used to treat the rat diarrhea. The control group was gavaged with 1.5ml of 0.2g / ml senna and then not treated. The cumulative number of diarrhea in the rats within 6h was observed. The rat stools can be divided into 5 types: normal stool, normal appearance but high water content stool, abnormal appearance soft stool, watery stool, and mucus stool. The first two types are considered normal stools, and the last three types are diarrhea stools. The specific test results are shown in the table below:

[0033] As can be seen from the above table, the probiotic chewable tablets prepared in Examples 1 to 3 have a good therapeutic effect on diarrhea in rats, significantly reducing the number of diarrhea in rats, and the rats can basically recover after 6 hours of treatment; the probiotic chewable tablets prepared in Comparative Example 1 are added with protamine, sodium polymannuronate and puerarin. Compared with the examples, the therapeutic effect of diarrhea in rats is average, which may be because puerarin is not encapsulated, and the stability of puerarin in gastrointestinal fluid is reduced, resulting in a decrease in the therapeutic effect of diarrhea; the probiotic chewable tablets prepared in Comparative Example 2 are not added with puerarin-loaded sustained-release microspheres. Compared with the examples, the number of diarrhea in rats is more, and the therapeutic effect is slow; the control group does not treat the rats with diarrhea, and the recovery effect of the rats is poor.

[0034] The above content is merely an example and explanation of the concept of the present invention. Those skilled in the art may make various modifications or additions to the described specific embodiments or replace them in a similar manner. As long as they do not deviate from the concept of the invention or exceed the scope defined by the claims, they should all fall within the scope of protection of the present invention.

Claims

1. A method for producing a composite probiotic chewable tablet, characterized in that: The probiotic chewable tablet comprises the following raw materials in parts by weight: 30 to 50 parts of probiotic powder, 4 to 8 parts of puerarin-loaded sustained-release microspheres, 15 to 25 parts of erythritol, 10 to 20 parts of isomaltooligosaccharides, 10 to 15 parts of lemon powder, and 1 to 2 parts of magnesium stearate; The production method comprises the following steps: (1) Erythritol, oligomaltodextrose and lemon powder were added to a grinder for grinding and sieving respectively. The ground materials were added to a mixer and stirred for 25 to 35 minutes. Puerarin sustained-release microspheres were then added and mixed evenly. Deionized water was then slowly added. Under the action of continuous stirring, the materials were gradually moistened. The materials were then kneaded into a mass and dispersed to obtain a soft material. (2) The obtained soft material is placed in a swing granulator for granulation. After granulation, it is placed in a blast drying oven at 55-65°C for drying. The dried granules are sieved through a 12-16 mesh sieve to obtain dry granules. (3) Magnesium stearate and probiotic powder are added to the dry granules, mixed evenly, and then compressed using a single punch tablet press to prepare probiotic chewable tablets.

2. The method for producing a composite probiotic chewable tablet according to claim 1, characterized in that: In step (1), the mesh size of the sieving is 80 to 120 meshes.

3. The method for producing a composite probiotic chewable tablet according to claim 1, characterized in that: In step (2), the drying end point is a particle moisture content of 1 to 4%.

4. The method for producing a composite probiotic chewable tablet according to claim 1, wherein: In step (3), the probiotic powder is Bifidobacterium lactis and Lactobacillus rhamnosus, with a mass ratio of 3:

1.

5. The method for producing a composite probiotic chewable tablet according to claim 1, characterized in that: The preparation method of the puerarin-loaded sustained-release microspheres comprises the following steps: A1: Mix protamine with deionized water and disperse them by ultrasonication for 40-50 minutes to prepare a protamine solution; mix modified sodium polymannuronate with deionized water and disperse them by ultrasonication for 30-40 minutes to prepare a modified sodium polymannuronate solution; A2: Add puerarin to the protamine solution and mix well. Then add the modified sodium polymannuronate solution and emulsify at 900-1100 r / min for 3-5 minutes using a high-speed disperser. Then stir at 35-45°C and 300-500 r / min for 20-40 minutes. Cool to 8-12°C, adjust the pH value of the system to neutral with sodium hydroxide solution, add a curing agent, cure for 5-7 hours, let stand, filter, and freeze-dry to obtain puerarin-loaded sustained-release microspheres.

6. The method for producing a composite probiotic chewable tablet according to claim 5, characterized in that: In step A2, the mass fraction of the sodium hydroxide solution is 10% to 50%.

7. The method for producing a composite probiotic chewable tablet according to claim 5, characterized in that: In step A2, the curing agent is transglutaminase.

8. The method for producing a composite probiotic chewable tablet according to claim 5, characterized in that: The preparation method of the modified sodium polymannuronate solution comprises the following steps: Sodium polymannuronate is added to deionized water, mechanically stirred evenly, cysteine ​​and N,N'-dicyclohexylcarbodiimide are added, the temperature is raised to 90-110°C under stirring, kept warm for 5-7 hours, cooled and discharged, and the modified sodium polymannuronate can be obtained.

9. The method for producing a composite probiotic chewable tablet according to claim 8, characterized in that: The mass ratio of the sodium polymannuronate to cysteine ​​is 1:0.1-0.

3.

10. A composite probiotic chewable tablet, characterized in that: The method is as claimed in claim 1.

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