An intestinal sustained-release acidifier and its preparation method

Abstract

This invention discloses an intestinal sustained-release acidifier, the raw materials of which include: citric acid, fumaric acid, lactic acid, phosphoric acid, sodium butyrate, self-assembled silica, polyethylene glycol, and hydrogenated palm oil; the mass ratio of citric acid, fumaric acid, lactic acid, phosphoric acid, sodium butyrate, self-assembled silica, polyethylene glycol, and hydrogenated palm oil is 5-10:5-15:5-15:1-5:1-5:1-5:4-10:1-3:5-15. This invention also discloses a method for preparing the above-mentioned intestinal sustained-release acidifier, comprising: mixing lactic acid and phosphoric acid evenly, then adding self-assembled silica and ultrasonically dispersing to obtain a pre-formulated material; ultra-finely pulverizing citric acid, fumaric acid, and sodium butyrate, sieving, adding polyethylene glycol and stirring evenly, adding the pre-formulated material and stirring, and spray granulation to obtain pre-formed microspheres; heating hydrogenated palm oil to melt, adding the pre-formed microspheres, stirring evenly at 100-120°C, and cryogenically spraying to obtain the intestinal sustained-release acidifier.

Description

Technical Field

[0001] This invention relates to the field of feed acidifier technology, and in particular to an intestinal slow-release acidifier and its preparation method. Background Technology

[0002] As research into feed and its additives deepens, the negative effects of feed additives have become increasingly apparent. In particular, the excessive use of antibiotics as feed additives can lead to the proliferation of drug-resistant bacteria, posing a threat to human and animal health and drawing widespread attention. Acidifiers, a commonly used feed additive, can lower the pH value of the animal's gastrointestinal tract, thereby improving gastrointestinal digestive activity, promoting nutrient digestion and absorption, preventing diarrhea, reducing the impact of heat stress, and lowering the risk of transmission of pathogenic bacteria such as Escherichia coli and Salmonella.

[0003] Acidifiers include inorganic and organic acids. Inorganic acids have strong acidity and relatively low addition costs, but they can damage the gastric mucosa and inhibit gastric acid secretion during use, thus affecting the normal development of the animal's gastrointestinal tract. Organic acids, on the other hand, have good flavor, and some can directly enter the tricarboxylic acid cycle, making them more commonly used in production, but their efficacy is not as good as that of inorganic acids. Acidifiers have many functions and effects, and compound acidifiers can effectively overcome the shortcomings or defects of single acidifiers by combining different single acids, thereby improving the application effect of acidifiers, which is becoming the development trend of acidifiers.

[0004] In existing technologies, in order to mitigate the corrosiveness, strong irritant and unstable effects of acidifiers, packaging materials are added to the surface of the acidifier for encapsulation. This allows the acidifier to be slowly released in the digestive environment, minimizing its impact on the animal's own gastric acid and pepsinogen secretion. However, most of it is absorbed in the stomach and very little reaches the animal's small intestine and other posterior digestive tracts, thus failing to fully exert its antibacterial and growth-promoting effects in the posterior digestive tract. Summary of the Invention

[0005] Based on the technical problems existing in the background art, the present invention proposes an intestinal sustained-release acidifier and its preparation method.

[0006] An intestinal sustained-release acidifier, the raw materials of which include: citric acid, fumaric acid, lactic acid, phosphoric acid, sodium butyrate, self-assembled silica, polyethylene glycol, and hydrogenated palm oil; the mass ratio of citric acid, fumaric acid, lactic acid, phosphoric acid, sodium butyrate, self-assembled silica, polyethylene glycol, and hydrogenated palm oil is 5-10:5-15:5-15:1-5:1-5:1-5:4-10:1-3:5-15.

[0007] Preferably, the self-assembled silica microspheres are prepared by the following steps: resorcinol is added to water and stirred until homogeneous; surfactant F127 is added and stirred until homogeneous; formaldehyde solution is added and stirred for 5-10 min; 1,6-hexanediamine and tetraethyl orthosilicate are added and stirred until the system turns milky white; ammonia solution is added and the mixture is refluxed at 70-80℃ and stirred for 5-10 h; tetraethyl orthosilicate is added and stirred for 10-20 h; the mixture is centrifuged, washed, dried, and calcined at 600-650℃ for 1-2 h under argon atmosphere protection to obtain self-assembled silica microspheres.

[0008] Preferably, the self-assembled silica microspheres have a particle size of 100-500 nm and a specific surface area of ​​1420-1580 m². 2 / g, pore volume 0.7-0.75cm 3 / g.

[0009] Preferably, the formaldehyde solution has a mass fraction of 30-35%, and the ammonia concentration is 0.5-1.2 mol / L.

[0010] Preferably, the mass ratio of resorcinol, surfactant F127, formaldehyde solution, 1,6-hexanediamine, tetraethyl orthosilicate, ammonia, and tetraethyl orthosilicate is 2-5:0.1-0.6:1-2:1-2:0.1-1:1-2:2-6.

[0011] The preparation method of the above-mentioned intestinal sustained-release acidifier includes the following steps:

[0012] S1. Mix lactic acid and phosphoric acid evenly, then add self-assembled silica and disperse ultrasonically to obtain a preform.

[0013] S2. Citrate citric acid, fumaric acid and sodium butyrate into ultrafine powder, sieve, add polyethylene glycol and stir evenly, add pre-made material and stir for 1-2 hours, then spray granulate to obtain pre-made microspheres.

[0014] S3. After heating the hydrogenated palm oil to melt, add the pre-made microspheres, stir evenly at 100-120℃, and then freeze spray to obtain the intestinal slow-release acidifier.

[0015] Preferably, in S1, the ultrasonic dispersion time is 1-2 hours and the ultrasonic frequency is 5-15 kHz.

[0016] Preferably, the pre-fabricated microspheres obtained in S2 have a mesh size of 100.

[0017] Preferably, the intestinal slow-release acidifier obtained in S3 has a mesh size of 30 mesh.

[0018] The application of the above-mentioned intestinal slow-release acidifier in the preparation of drugs for treating diarrhea in piglets.

[0019] The technical effects of this invention are as follows:

[0020] This invention uses resorcinol, formaldehyde, and 1,6-hexanediamine as raw materials, and polymerizes them with ammonia catalysis to form polymer microspheres. Since the tetrahedral structure of the polymer microspheres has a similar tetrahedral structure and a similar condensation rate to the hydrolysis products of silicates, a certain amount of tetraethyl orthosilicate is added during the polymerization process to combine an appropriate amount of silica nanoparticles into the polymer microsphere structure, that is, to self-assemble silica nanoparticles in the polymer microsphere structure. Further addition of tetraethyl orthosilicate results in the silica nanoparticles formed by hydrolysis having extremely high affinity on the surface of the polymer microspheres, causing them to be further deposited on the surface of the polymer microspheres. After high-temperature pyrolysis, self-assembled silica microspheres with extremely rich pores are obtained.

[0021] During the calcination process of self-assembled silica microspheres, the silica deposited on the surface can construct discrete confined spaces on the surface of the microspheres. Therefore, the silica is not only not easy to agglomerate during the calcination process, but also disperses stably in aqueous solution. Since the self-assembled silica microspheres have abundant open mesopores, when combined with lactic acid and phosphoric acid, the self-assembled silica microspheres can adsorb and contain lactic acid and phosphoric acid under ultrasonic action, with a large adsorption capacity and good adsorption stability.

[0022] This application continues to use citric acid, fumaric acid, and sodium butyrate for ultrafine pulverization, which are then combined with pre-formulated materials under the action of polyethylene glycol. The mixture is further adsorbed and bound into the structure of self-assembled silica microspheres. Then, palm oil is melted and coated to form an intestinal sustained-release acidifier. This not only remains intact in the stomach but also dissolves in the intestine, especially reaching the lower part of the intestine, where it can better exert its acidifying and antibacterial effects in the animal's digestive tract. Moreover, it can form a multi-level sustained release of lactic acid, phosphoric acid, citric acid, and fumaric acid, with higher sustained-release stability and an antibacterial rate of over 85%, effectively reducing the dosage required.

[0023] This invention employs self-assembled silica to adsorb and then coat lactic acid, phosphoric acid, citric acid, and fumaric acid. This not only ensures that the complex acids remain intact in the stomach but also dissolve and release in the intestine. The dissolution process of lactic acid, phosphoric acid, citric acid, and fumaric acid is controllable, effectively prolonging their action time in the intestine, improving bioavailability, and reducing dosage. Furthermore, it can regulate the dissolution order of lactic acid, phosphoric acid, citric acid, and fumaric acid in the intestine, better adjusting intestinal pH, enhancing the activity of various digestive enzymes, and promoting the immune function of young animals. Attached Figure Description

[0024] Figure 1 The graph shows the pH changes of the intestinal sustained-release acidifier obtained in Example 5 in simulated gastric and intestinal fluids.

[0025] Figure 2 This is a comparison chart of the encapsulation efficiency of the intestinal sustained-release acidifiers obtained in Example 5 and Comparative Examples 1-2.

[0026] Figure 3 The graph shows the changes in the antibacterial rate of the intestinal sustained-release acidifiers obtained in Example 5 and Comparative Examples 1-2 in simulated intestinal fluid.

[0027] Figure 4 This is a comparison chart of antibody levels in piglets from Example 5, Comparative Examples 1-2, and the blank control group. Detailed Implementation

[0028] The technical solution of the present invention will now be described in detail through specific embodiments.

[0029] Example 1

[0030] An intestinal slow-release acidifier, the raw materials of which include: 5 kg of citric acid, 5 kg of fumaric acid, 5 kg of lactic acid, 1 kg of phosphoric acid, 1 kg of sodium butyrate, 4 kg of self-assembled silica, 1 kg of polyethylene glycol, and 5 kg of hydrogenated palm oil.

[0031] The self-assembled silica microspheres were prepared as follows: 2 kg of resorcinol was added to 10 kg of water and stirred until homogeneous. 0.1 kg of surfactant F127 was added and stirred until homogeneous. 1 kg of 30% formaldehyde aqueous solution was added and stirred at 100 r / min for 5 min. 1 kg of 1,6-hexanediamine and 0.1 kg of tetraethyl orthosilicate were added and stirred until the system turned milky white. 1 kg of 0.5 mol / L ammonia solution was added and refluxed at 70℃ for 5 h. 2 kg of tetraethyl orthosilicate was added and stirred for 10 h. The mixture was centrifuged, washed with anhydrous ethanol and deionized water, dried, and placed in a muffle furnace. Under argon atmosphere protection, it was calcined at 600℃ for 1 h to obtain the self-assembled silica microspheres.

[0032] The preparation method of the above-mentioned intestinal sustained-release acidifier includes the following steps:

[0033] S1. Mix lactic acid and phosphoric acid evenly, then add self-assembled silica and ultrasonically disperse for 1 hour at an ultrasonic frequency of 5 kHz to obtain the preform.

[0034] S2. Citrate citric acid, fumaric acid, and sodium butyrate into ultrafine powders, pass them through a 200-mesh sieve, add polyethylene glycol and stir evenly, add pre-made material, stir at 1000 r / min for 1 h, and spray granulate to obtain pre-made microspheres with a particle size of 100 mesh.

[0035] S3. After heating the hydrogenated palm oil to melt, add the pre-made microspheres and stir evenly at 100°C. Then, freeze spray to obtain an intestinal slow-release acidifier with a particle size of 30 mesh.

[0036] Example 2

[0037] An intestinal sustained-release acidifier, the raw materials of which include: 10 kg of citric acid, 15 kg of fumaric acid, 15 kg of lactic acid, 5 kg of phosphoric acid, 5 kg of sodium butyrate, 10 kg of self-assembled silica, 3 kg of polyethylene glycol, and 15 kg of hydrogenated palm oil.

[0038] The self-assembled silica microspheres were prepared as follows: 5 kg of resorcinol was added to 30 kg of water and stirred until homogeneous. 0.6 kg of surfactant F127 was added and stirred until homogeneous. 2 kg of 35% formaldehyde aqueous solution was added and stirred at 300 r / min for 10 min. 2 kg of 1,6-hexanediamine and 1 kg of tetraethyl orthosilicate were added and stirred until the system turned milky white. 2 kg of 1.2 mol / L ammonia solution was added and refluxed at 80℃ for 10 h. 6 kg of tetraethyl orthosilicate was added and stirred for 20 h. The mixture was centrifuged, washed with anhydrous ethanol and deionized water, dried, and placed in a muffle furnace. Under argon atmosphere protection, it was calcined at 650℃ for 2 h to obtain the self-assembled silica microspheres.

[0039] The preparation method of the above-mentioned intestinal sustained-release acidifier includes the following steps:

[0040] S1. Mix lactic acid and phosphoric acid evenly, then add self-assembled silica and ultrasonically disperse for 2 hours at an ultrasonic frequency of 15 kHz to obtain the preform.

[0041] S2. Citrate citric acid, fumaric acid, and sodium butyrate into ultrafine powders, pass them through a 200-mesh sieve, add polyethylene glycol and stir evenly, add pre-made material, stir at 2000 r / min for 2 hours, and spray granulate to obtain pre-made microspheres with a particle size of 100 mesh.

[0042] S3. After heating the hydrogenated palm oil to melt, add the pre-made microspheres and stir evenly at 120°C. Then, freeze spray to obtain an intestinal slow-release acidifier with a particle size of 30 mesh.

[0043] Example 3

[0044] An intestinal slow-release acidifier, the raw materials of which include: 7 kg citric acid, 12 kg fumaric acid, 8 kg lactic acid, 4 kg phosphoric acid, 2 kg sodium butyrate, 8 kg self-assembled silica, 1.5 kg polyethylene glycol, and 12 kg hydrogenated palm oil.

[0045] The self-assembled silica microspheres were prepared as follows: 3 kg of resorcinol was added to 25 kg of water and stirred until homogeneous. 0.2 kg of surfactant F127 was added and stirred until homogeneous. 1.7 kg of 32% formaldehyde aqueous solution was added and stirred at 260 r / min for 7 min. 1.7 kg of 1,6-hexanediamine and 0.2 kg of tetraethyl orthosilicate were added and stirring continued until the system turned milky white. 1.7 kg of 0.8 mol / L ammonia water was added and refluxed at 77℃ for 6 h. 5 kg of tetraethyl orthosilicate was added and stirring continued for 12 h. The mixture was centrifuged, washed with anhydrous ethanol and deionized water, dried, and placed in a muffle furnace. Under argon atmosphere protection, it was calcined at 640℃ for 70 min to obtain the self-assembled silica microspheres.

[0046] The preparation method of the above-mentioned intestinal sustained-release acidifier includes the following steps:

[0047] S1. Mix lactic acid and phosphoric acid evenly, then add self-assembled silica and ultrasonically disperse for 110 min at an ultrasonic frequency of 6 kHz to obtain the preform.

[0048] S2. Citrate citric acid, fumaric acid, and sodium butyrate into ultrafine powders, pass them through a 200-mesh sieve, add polyethylene glycol and stir evenly, add pre-made material, stir at 1800 r / min for 80 min, and spray granulate to obtain pre-made microspheres with a particle size of 100 mesh.

[0049] S3. After heating the hydrogenated palm oil to melt, add the pre-made microspheres and stir evenly at 115°C. Then, freeze spray to obtain an intestinal slow-release acidifier with a particle size of 30 mesh.

[0050] Example 4

[0051] An intestinal slow-release acidifier, the raw materials of which include: 9 kg citric acid, 8 kg fumaric acid, 12 kg lactic acid, 2 kg phosphoric acid, 4 kg sodium butyrate, 6 kg self-assembled silica, 2.5 kg polyethylene glycol, and 8 kg hydrogenated palm oil.

[0052] The self-assembled silica microspheres were prepared as follows: 4 kg of resorcinol was added to 15 kg of water and stirred until homogeneous. 0.5 kg of surfactant F127 was added and stirred until homogeneous. 1.3 kg of 34% formaldehyde aqueous solution was added and stirred at 150 r / min for 9 min. 1.3 kg of 1,6-hexanediamine and 0.8 kg of tetraethyl orthosilicate were added and stirring continued until the system turned milky white. 1.3 kg of 1 mol / L ammonia solution was added and the mixture was refluxed and stirred at 73℃ for 8 h. 3 kg of tetraethyl orthosilicate was added and stirring continued for 18 h. The mixture was centrifuged, washed with anhydrous ethanol and deionized water, dried, and placed in a muffle furnace. Under argon atmosphere protection, the mixture was calcined at 620℃ for 100 min to obtain the self-assembled silica microspheres.

[0053] The preparation method of the above-mentioned intestinal sustained-release acidifier includes the following steps:

[0054] S1. Mix lactic acid and phosphoric acid evenly, then add self-assembled silica and ultrasonically disperse for 80 minutes at an ultrasonic frequency of 12 kHz to obtain the preform.

[0055] S2. Citrate citric acid, fumaric acid, and sodium butyrate into ultrafine powders, pass them through a 200-mesh sieve, add polyethylene glycol and stir evenly, add pre-made material, stir at 1200 r / min for 100 min, and spray granulate to obtain pre-made microspheres with a particle size of 100 mesh.

[0056] S3. After heating the hydrogenated palm oil to melt, add the pre-made microspheres and stir evenly at 105°C. Then, freeze spray to obtain an intestinal slow-release acidifier with a particle size of 30 mesh.

[0057] Example 5

[0058] An intestinal sustained-release acidifier, the raw materials of which include: 8 kg of citric acid, 10 kg of fumaric acid, 10 kg of lactic acid, 3 kg of phosphoric acid, 3 kg of sodium butyrate, 7 kg of self-assembled silica, 2 kg of polyethylene glycol, and 10 kg of hydrogenated palm oil.

[0059] The self-assembled silica microspheres were prepared as follows: 3.5 kg of resorcinol was added to 20 kg of water and stirred until homogeneous. 0.35 kg of surfactant F127 was added and stirred until homogeneous. 1.5 kg of 33% formaldehyde aqueous solution was added and stirred at 200 r / min for 8 min. 1.5 kg of 1,6-hexanediamine and 0.5 kg of tetraethyl orthosilicate were added and stirring continued until the system turned milky white. 1.5 kg of 0.9 mol / L ammonia water was added and refluxed at 75℃ for 7 h. 4 kg of tetraethyl orthosilicate was added and stirring continued for 15 h. The mixture was centrifuged, washed with anhydrous ethanol and deionized water, dried, and placed in a muffle furnace. Under argon atmosphere protection, it was calcined at 630℃ for 90 min to obtain the self-assembled silica microspheres.

[0060] The obtained self-assembled silica microspheres were found to have a size of 246 nm, a specific surface area of ​​1496.8 m² / g, and a micropore volume of 0.744 cm³. 3 / g; Further testing of the pore size distribution of the obtained self-assembled silica microspheres revealed that the obtained self-assembled silica microspheres have two types of micropores: 0.2-0.4 nm and 0.8-1.2 nm. The applicant believes that the 0.2-0.4 nm micropores originate from its shell layer, while the 0.8-1.2 nm micropores originate from its core layer.

[0061] The preparation method of the above-mentioned intestinal sustained-release acidifier includes the following steps:

[0062] S1. Mix lactic acid and phosphoric acid evenly, then add self-assembled silica and ultrasonically disperse for 90 minutes at an ultrasonic frequency of 9kHz to obtain the preform.

[0063] S2. Citrate citric acid, fumaric acid, and sodium butyrate into ultrafine powders, pass them through a 200-mesh sieve, add polyethylene glycol and stir evenly, add pre-made material, stir at 1500 r / min for 90 min, and spray granulate to obtain pre-made microspheres with a particle size of 100 mesh.

[0064] S3. After heating the hydrogenated palm oil to melt, add the pre-made microspheres and stir evenly at 110°C. Then, freeze spray to obtain an intestinal slow-release acidifier with a particle size of 30 mesh.

[0065] The intestinal sustained-release acidifier obtained in Example 5 was placed in 200 mL of hydrochloric acid solution (pH=2.0, simulating the gastric juice system) and 200 mL of PBS buffer solution (pH=7.2, simulating the intestinal system), respectively, and stirred at a constant temperature of 37°C at a speed of 80 r / min. The pH value of the solution was detected at regular intervals.

[0066] like Figure 1 As shown, the intestinal sustained-release acidifier obtained in Example 5, when immersed in simulated gastric juice, showed almost no change in pH, indicating that the capsule of the intestinal sustained-release acidifier obtained in Example 5 did not rupture and could remain intact in the stomach. However, when the intestinal sustained-release acidifier obtained in Example 5 was immersed in simulated intestinal juice, the capsule ruptured, releasing the complex acid contents, and the pH value slowly decreased. The applicant believes that this is because the self-assembled silica microspheres with abundant open mesopores sequentially adsorb and contain lactic acid, phosphoric acid, citric acid, and fumaric acid, allowing the complex acid to be slowly released in the intestinal environment. This not only effectively prolongs the action time in the intestine, improves bioavailability, and reduces the dosage, but also regulates the dissolution order of lactic acid, phosphoric acid, citric acid, and fumaric acid in the intestine, better adjusting the intestinal pH, improving the activity of various digestive enzymes, and promoting the immune performance of young animals.

[0067] Comparative Example 1

[0068] An intestinal sustained-release acidifier, the raw materials of which include: 8 kg of citric acid, 10 kg of fumaric acid, 10 kg of lactic acid, 3 kg of phosphoric acid, 3 kg of sodium butyrate, 7 kg of self-assembled silica, 2 kg of polyethylene glycol, and 10 kg of hydrogenated palm oil.

[0069] The self-assembled silica microspheres were prepared as follows: 3.5 kg of resorcinol was added to 20 kg of water and stirred until homogeneous. 0.35 kg of surfactant F127 was added and stirred until homogeneous. 1.5 kg of 33% formaldehyde aqueous solution was added and stirred at 200 r / min for 8 min. 1.5 kg of 1,6-hexanediamine and 0.5 kg of tetraethyl orthosilicate were added and stirring continued until the system turned milky white. 1.5 kg of 0.9 mol / L ammonia water was added and refluxed at 75℃ for 7 h. 4 kg of tetraethyl orthosilicate was added and stirring continued for 15 h. The mixture was centrifuged, washed with anhydrous ethanol and deionized water, dried, and placed in a muffle furnace. Under argon atmosphere protection, it was calcined at 630℃ for 90 min to obtain the self-assembled silica microspheres.

[0070] The preparation method of the above-mentioned intestinal sustained-release acidifier includes the following steps:

[0071] S1. Citrate citric acid, fumaric acid, and sodium butyrate into ultrafine powders, pass them through a 200-mesh sieve, add lactic acid and phosphoric acid and mix evenly, then add polyethylene glycol and self-assembled silica and ultrasonically disperse for 90 minutes at an ultrasonic frequency of 9kHz, and spray granulate to obtain pre-made microspheres with a particle size of 100 mesh.

[0072] S2. After heating the hydrogenated palm oil to melt, add the pre-made microspheres and stir evenly at 110°C. Then, freeze spray to obtain an intestinal slow-release acidifier with a particle size of 30 mesh.

[0073] Comparative Example 2

[0074] An intestinal slow-release acidifier, the raw materials of which include: 8 kg of citric acid, 10 kg of fumaric acid, 10 kg of lactic acid, 3 kg of phosphoric acid, 3 kg of sodium butyrate, 7 kg of nano-silica, 2 kg of polyethylene glycol, and 10 kg of hydrogenated palm oil.

[0075] The preparation method of the above-mentioned intestinal sustained-release acidifier includes the following steps:

[0076] S1. Mix lactic acid and phosphoric acid evenly, then add nano-silica and ultrasonically disperse for 90 minutes at an ultrasonic frequency of 9kHz to obtain the preform.

[0077] S2. Citrate citric acid, fumaric acid, and sodium butyrate into ultrafine powders, pass them through a 200-mesh sieve, add polyethylene glycol and stir evenly, add pre-made material, stir at 1500 r / min for 90 min, and spray granulate to obtain pre-made microspheres with a particle size of 100 mesh.

[0078] S3. After heating the hydrogenated palm oil to melt, add the pre-made microspheres and stir evenly at 110°C. Then, freeze spray to obtain an intestinal slow-release acidifier with a particle size of 30 mesh.

[0079] The intestinal sustained-release acidifiers obtained in Example 5 and Comparative Examples 1-2 were placed in PBS buffer solution at pH 7.2 and placed in a 37°C constant temperature water bath. The solution was stirred with a magnetic stirrer at 80 rpm to ensure complete release of citric acid. Every 0.5 hours, 5 mL of the buffer solution was pipetted into pre-labeled centrifuge tubes and centrifuged at 5000 rpm for 30 minutes. The tubes were then diluted 30 times with distilled water, and the absorbance was measured using an atomic absorption spectrophotometer. The absorbance was then converted to the citric acid content in each buffer solution to calculate the encapsulation efficiency.

[0080] Encapsulation efficiency = Citric acid content in microspheres / Initial citric acid dosage × 100%

[0081] like Figure 2 As shown, the encapsulation rates of the intestinal sustained-release acidifiers obtained in Example 5 and Comparative Example 1 are similar, but superior to those in Comparative Example 2. The applicant believes this is because nano-silica cannot adsorb complex acids, while this application uses self-assembled silica microspheres with abundant open mesopores to sequentially adsorb and contain lactic acid, phosphoric acid, citric acid, and fumaric acid, resulting in extremely high encapsulation rates.

[0082] The intestinal slow-release acidifiers obtained in Example 5 and Comparative Examples 1-2 were added at a dosage of 4% to PBS buffer solution (simulated intestinal fluid) at pH 7.2. 2 mL of the solution was added to a test tube containing 8 mL of culture medium, followed by 100 μL of Escherichia coli suspension cultured to the logarithmic growth phase. The mixture was treated in a water bath at 37°C and a stirring speed of 220 r / min. The absorbance at 630 nm was measured using a visible spectrophotometer at 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12 h, 14 h, 16 h, and 18 h. The antibacterial rate was calculated using the following formula.

[0083] Antibacterial rate = (OD1 - OD) / OD × 100%

[0084] OD is the absorbance of the sample; OD1 is the absorbance of the bacterial culture medium without intestinal slow-release acidifier.

[0085] like Figure 3 As shown, the intestinal slow-release acidifier obtained in Example 5 is slowly released in the intestine, providing long-lasting bactericidal and bacteriostatic effects. The antibacterial rate steadily increases within 14 hours, reaching a maximum of over 85%.

[0086] However, the intestinal sustained-release acidifier obtained in Comparative Example 1 showed a steady increase in antibacterial rate in the first 6 hours, followed by a decline. The applicant believes that this is because the application, through the formation of multi-level sustained release of lactic acid, phosphoric acid, citric acid, and fumaric acid, regulates the dissolution order of the complex acid in the intestine, thereby better adjusting the intestinal pH and improving the activity of various digestive enzymes.

[0087] The intestinal sustained-release acidifier obtained in Comparative Example 2 disintegrated and released in the intestine, causing its antibacterial rate to reach its highest level initially, and then rapidly decreased, dropping to less than 10% after 8 hours.

[0088] A comparative feeding trial was conducted at a breeding base in Jiaxing. 120 healthy Duroc × Large White × Landrace crossbred piglets were randomly divided into 4 groups, with 3 replicates per group and 10 piglets per replicate. Group 5 (Example 5), Comparative Example 1, and Comparative Example 2 were fed with the intestinal slow-release acidifiers obtained in Example 5 and Comparative Example 1, respectively, added to their daily feed. The blank control group was fed only the daily feed. During the trial, pigs were fed routinely with free access to feed and water. After 4 weeks, the pigs in each group were weighed, and feed consumption and feed conversion ratio were calculated. The diarrhea rate during the trial was observed and statistically analyzed.

[0089] Diarrhea rate = (Total number of piglets with diarrhea per day during the experiment) / (Number of piglets in the experiment × Number of days in the experiment) × 100%

[0090] Example 5 group Comparative Example 1 Comparative Example 2 Blank control group Average daily weight gain, g 666.34 621.95 603.39 584.27 Average daily material consumption, g 1126.12 1082.19 1128.34 1320.45 Material weight ratio 1.69 1.74 1.87 2.26 Diarrhea rate, % 2.98 5.71 10.24 17.26

[0091] As shown in the table above, the use of acidifiers in Example 5, Comparative Example 1, and Comparative Example 2 resulted in better average daily weight gain and diarrhea rate for piglets compared to the blank control group, while the feed conversion ratio was lower. Specifically, the diarrhea rate and feed conversion ratio of Example 5 were significantly lower than those of Comparative Example 1 and Comparative Example 2 (P < 0.05), confirming that the intestinal slow-release acidifier obtained in this invention can adjust intestinal pH, increase the activity of various digestive enzymes, promote piglet growth, and improve immune performance through multi-level slow release in the intestine.

[0092] Collect piglet serum and test antibody levels. Figure 4 As shown, the intestinal slow-release acidifier obtained in Example 5 can effectively increase the antibody level in the serum of piglets, thereby improving their immune performance.

[0093] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. An intestinal sustained-release acidifier, characterized in that, Its raw materials include: citric acid, fumaric acid, lactic acid, phosphoric acid, sodium butyrate, self-assembled silica, polyethylene glycol, and hydrogenated palm oil; the mass ratio of citric acid, fumaric acid, lactic acid, phosphoric acid, sodium butyrate, self-assembled silica, polyethylene glycol, and hydrogenated palm oil is 5-10:5-15:5-15:1-5:1-5:4-10:1-3:5-15; The self-assembled silica microspheres have a particle size of 100-500 nm and a specific surface area of ​​1420-1580 m². 2 / g, pore volume 0.7-0.75cm 3 / g; Self-assembled silica microspheres were prepared by the following steps: Resorcinol was added to water and stirred until homogeneous; surfactant F127 was added and stirred until homogeneous; formaldehyde solution was added and stirred for 5-10 min; 1,6-hexanediamine and tetraethyl orthosilicate were added and stirred until the system turned milky white; ammonia solution was added and the mixture was refluxed at 70-80℃ and stirred for 5-10 h; tetraethyl orthosilicate was added and stirred for 10-20 h; centrifuged, washed, dried, and calcined at 600-650℃ for 1-2 h under argon atmosphere protection to obtain self-assembled silica microspheres. The formaldehyde solution has a mass fraction of 30-35%, and the ammonia concentration is 0.5-1.2 mol / L. The mass ratio of resorcinol, surfactant F127, formaldehyde solution, 1,6-hexanediamine, tetraethyl orthosilicate, ammonia, and tetraethyl orthosilicate is 2-5:0.1-0.6:1-2:1-2:0.1-1:1-2:2-6.

2. A method for preparing the intestinal sustained-release acidifier as described in claim 1, characterized in that, Includes the following steps: S1. Mix lactic acid and phosphoric acid evenly, then add self-assembled silica and disperse ultrasonically to obtain a preform. S2. Citrate citric acid, fumaric acid and sodium butyrate into ultrafine powder, sieve, add polyethylene glycol and stir evenly, add pre-made material and stir for 1-2 hours, then spray granulate to obtain pre-made microspheres. S3. After heating the hydrogenated palm oil to melt, add the pre-made microspheres, stir evenly at 100-120℃, and then freeze spray to obtain the intestinal slow-release acidifier.

3. The method for preparing the intestinal sustained-release acidifier according to claim 2, characterized in that, In S1, the ultrasonic dispersion time is 1-2 hours and the ultrasonic frequency is 5-15 kHz.

4. The method for preparing the intestinal sustained-release acidifier according to claim 2, characterized in that, The pre-fabricated microspheres obtained by S2 have a mesh size of 100.

5. The method for preparing the intestinal sustained-release acidifier according to claim 2, characterized in that, The intestinal slow-release acidifier obtained from S3 has a mesh size of 30 mesh.

6. The use of the intestinal slow-release acidifier as described in claim 1 in the preparation of a drug for treating diarrhea in piglets.

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