Slow-release coated copper sulfate for preventing piglet diarrhea as well as preparation method and application of slow-release coated copper sulfate

Abstract

The invention belongs to the technical field of feed additives, and particularly relates to slow-release coated copper sulfate for preventing piglet diarrhea as well as a preparation method and application of the slow-release coated copper sulfate. The invention provides slow-release coated copper sulfate which comprises a copper sulfate mixture, and a targeting layer and an enteric layer which are sequentially coated on the surface of the copper sulfate mixture, the copper sulfate mixture comprises copper sulfate, sodium alginate, beta-glucan and pregelatinized starch; the targeting layer is prepared from guar gum, chitosan, hydrophilic silicon dioxide, hydrophobic beewax, glycerol monoacetate and hemicellulose; the enteric-coated layer comprises hydrogenated vegetable oil, ethyl cellulose and lipophilic silicon dioxide. The slow-release coated copper sulfate is sequentially coated with multiple layers of membrane materials with specific functions, fixed-point accurate release of copper sulfate in cecum is achieved, holes in the layer surface can be uniform during release under the design of the targeting layer, the release rate of copper sulfate is uniform, and finally slow release and constant-speed release of copper sulfate can be achieved.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of feed additives, and particularly relates to a slow-release type coated copper sulfate for preventing diarrhea of piglets and a preparation method and application thereof. BACKGROUND

[0002] Copper sulfate is generally used for treating diarrhea of human or animal body, especially diarrhea related to copper deficiency, or as an additive in livestock breeding. This is because copper ions can help reduce intestinal secretions, inhibit the growth of pathogens such as bacteria and parasites, and correct copper deficiency caused by long-term diarrhea or malabsorption.

[0003] At present, the release position of copper sulfate in application is uncontrollable, resulting in low utilization. Copper sulfate is easy to dissolve in gastric acid, and copper ions are released and absorbed in large quantities in the stomach and upper small intestine. However, the diarrhea lesion is usually located in the lower small intestine or cecum, and copper sulfate is released in large quantities in the stomach before reaching the cecum, which is difficult to achieve the therapeutic effect. In addition, the released copper ions have astringent, corrosive and stimulating effect on the gastrointestinal mucosa, which can cause adverse reactions such as nausea, vomiting and abdominal pain. Long-term or high-dose use may even lead to acute or chronic copper poisoning.

[0004] In view of this problem, researchers consider selecting a carrier to help copper sulfate release at a specific site. However, there are still many problems to be solved to achieve safe, efficient and stable intestinal targeted therapy of copper sulfate. SUMMARY

[0005] The present application provides a slow-release type coated copper sulfate for preventing diarrhea of piglets and a preparation method and application thereof. The slow-release type coated copper sulfate is coated with multiple layers of specific functional film materials in sequence to achieve precise release of copper sulfate at the cecum, and under the design of the targeting layer, the holes on the surface of the layer are uniform when the copper sulfate mixture is released, so that the release rate of the copper sulfate mixture is uniform, and finally the constant release of copper sulfate can be achieved.

[0006] In order to achieve the above purpose, the present application provides the following technical scheme: The present application provides a slow-release type coated copper sulfate, comprising: a copper sulfate mixture, and a targeting layer and an enteric layer coated on the surface of the copper sulfate mixture in sequence; the copper sulfate mixture comprises copper sulfate, sodium alginate, beta-glucan and pregelatinized starch; the targeting layer comprises guar gum, chitosan, hydrophilic silicon dioxide, hydrophobic beeswax, glycerol monoacetate and hemicellulose; and the enteric layer comprises hydrogenated vegetable oil, ethyl cellulose and lipophilic silicon dioxide.

[0007] The present applicant considers that the copper sulfate can be coated to achieve slow release of copper sulfate. When the copper sulfate is coated, the present applicant finds that only a single coating cannot achieve the effect of slow release at a fixed point. Therefore, the present applicant considers that different special functional film layers are arranged to be compounded so that the copper sulfate can be released at the cecum position as much as possible.

[0008] Specifically, the use of the outer enteric layer enables the copper sulfate to avoid the attack of gastric acid and enables the final release point of the slow-release coated copper sulfate to fall in the intestinal tract. The targeting layer enables the copper sulfate to achieve constant speed and directional release in the cecum because of the special effect among the hydrophilic silicon dioxide, the hydrophobic beeswax and the glycerol monoacetate. The glycerol monoacetate can promote the uniform dispersion of the hydrophobic beeswax in the hydrophilic polysaccharide (guar gum / chitosan) matrix, and the plasticizing effect thereof prevents the film from being brittle due to the addition of rigid hydrophilic silicon dioxide particles and hydrophobic beeswax; the three together form an ideal functional film which is "flexible, dense and hydrophobic".

[0009] In addition, the glycerol monoacetate has dual functions of hydrophilicity and lipophilicity. On the one hand, the hydrophilicity enables the targeting layer to have holes on the surface when it finally contacts the cecum, so as to realize the exchange between the copper sulfate mixture particles and the cecum environment; on the other hand, the lipophilicity can enhance the solubility with the hydrophobic beeswax. The glycerol monoacetate and the hydrophobic beeswax can have dual functions of pore-forming and hydrophobicity, and when the pores are formed, the average pore size of the holes can be more balanced in the presence of the hydrophobic beeswax, and the contact time of the copper sulfate mixture particles with each site of the intestinal tract is more balanced. In addition, the copper sulfate is coated in sodium alginate, β-glucan and pre-gelatinized starch, so that the release position of the copper ions in the copper sulfate is fixed. Taking the copper sulfate mixture particles as the core, the copper ions can move in a nearly regular circumferential direction, slowly contact the large intestine through the uniform holes on the targeting layer, and finally achieve directional and constant speed release. In this way, the absorption efficiency of the intestinal tract to the copper ions reaches the highest, and the concentration level of the copper ions in the intestinal tract of the animal is stable, which will not cause the intestinal microecological balance disorder and unstable anti-diarrhea effect caused by high and low fluctuation of the concentration.

[0010] Preferably, the copper sulfate mixture includes 6-10 parts of copper sulfate, 18-25 parts of sodium alginate, 20-30 parts of β-glucan and 15-20 parts of pre-gelatinized starch by weight.

[0011] Here, the mass of the copper sulfate and the sodium alginate is the dry mass.

[0012] Preferably, the source of the copper sulfate is copper sulfate pentahydrate, anhydrous copper sulfate or basic copper sulfate.

[0013] The copper sulfate source here can be any material that can provide the key ingredient of copper sulfate, including but not limited to common copper sulfate pentahydrate, anhydrous copper sulfate or basic copper sulfate. After adding copper sulfate raw materials of different sources, the dry weight of copper sulfate is kept at the above-mentioned limited proportion to meet the needs of the present application.

[0014] Preferably, the targeting layer comprises 2-3.5 parts of guar gum, 2-3.5 parts of chitosan, 0.2-0.4 parts of hydrophilic silica, 1-2.5 parts of hydrophobic beeswax, 1-2.5 parts of glycerol monoacetate and 0.2-0.6 parts of hemicellulose by weight.

[0015] Preferably, the enteric layer comprises 6-10 parts of hydrogenated vegetable oil, 1-5 parts of ethyl cellulose and 0.1-0.5 parts of lipophilic silica by weight.

[0016] Preferably, in the slow-release coated copper sulfate, the content of copper sulfate is 8-15 wt%; and / or, the particle size of the copper sulfate mixture is 16-25 mesh; and / or, the particle size of the hydrophilic silica and the lipophilic silica is 5-10 μm.

[0017] Preferably, the thickness ratio of the targeting layer and the enteric layer is (9-11):(11-13).

[0018] The present application provides a preparation method of slow-release coated copper sulfate, comprising: S1. preparing a sodium alginate solution, then adding copper sulfate, β-glucan and pregelatinized starch in sequence, mixing uniformly, wet granulating and drying to obtain a copper sulfate mixture; S2. weighing guar gum, chitosan, hydrophilic silica, hydrophobic beeswax, glycerol monoacetate and hemicellulose, adding them into an ice acetic acid solution to mix, obtaining a film solution of the targeting layer; S3. weighing hydrogenated vegetable oil, ethyl cellulose and lipophilic silica, adding them into an organic solvent to mix, obtaining a film solution of the enteric layer; S4. coating the copper sulfate mixture with the film solution of the targeting layer and the film solution of the enteric layer in sequence to obtain slow-release coated copper sulfate.

[0019] Preferably, the concentration of the sodium alginate solution is 3-8 wt%; and / or, the wet granulation condition is that the stirring speed is 500-1000 r / min and the shear paddle is 100-300 r / min; and / or, the drying temperature is 40-60℃; and / or, the ice acetic acid solution is obtained by mixing ice acetic acid and water at a volume ratio of (2-5):95; And / or, first add guar gum to a glacial acetic acid solution under stirring at 500~1000 r / min, then add chitosan and hemicellulose to obtain mixture A; separately heat the glacial acetic acid solution to 60~70℃, add hydrophobic beeswax and glyceryl monoacetate to obtain mixture B; after cooling mixture B, mix it with mixture A, and then add hydrophilic silica to obtain the membrane solution for the targeting layer; And / or, the organic solvent is obtained by mixing methanol and chloroform in a volume ratio of (3~5):6; And / or, the coating conditions are: coating is completed at 30~40℃ at a coating rate of 10~20 mL / min.

[0020] The present invention also provides a feed additive, including a slow-release coated copper sulfate.

[0021] Preferably, the dosage of slow-release coated copper sulfate is 300~500 g / t.

[0022] The present invention also provides the application of the above-mentioned feed additive in the prevention of diarrhea in piglets.

[0023] Therefore, the present invention has the following beneficial effects: (1) The sustained-release coated copper sulfate provided by the present invention utilizes multiple layers of membrane materials with specific functions to sequentially coat the copper sulfate, thereby achieving precise release of copper sulfate at a fixed point in the cecum.

[0024] (2) The slow-release coated copper sulfate provided by the present invention can make the pores on its surface uniform during release by designing the target layer, thus realizing the slow release and constant rate release of copper sulfate.

[0025] (3) The target layer designed in this invention can precisely regulate the initiation and rate of copper sulfate release under the synergistic effect of amphiphilic compound dissolution, porous particle adsorption and channel formation, and natural wax material blocking. Attached Figure Description

[0026] Figure 1 This is a graph showing the scoring criteria for diarrhea rates.

[0027] Figure 2 This is a picture of experimental piglets. Detailed Implementation

[0028] The present invention will be further described below with reference to specific embodiments. Those skilled in the art will be able to implement the present invention based on these descriptions. Furthermore, the embodiments of the present invention described below are generally only some, not all, of the embodiments of the present invention. Therefore, all other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort should fall within the scope of protection of the present invention.

[0029]

Example

[0030] S2. Core capsule + Targeting layer Weigh out 3 parts by weight of guar gum, 3 parts by weight of chitosan, 0.3 parts by weight of hydrophilic silica (D50 5~10 μm), 1.6 parts by weight of hydrophobic beeswax, 1.8 parts by weight of glycerol monoacetate, and 0.3 parts by weight of hemicellulose. First, prepare a 100-part by weight dilute acetic acid solution by mixing deionized water and glacial acetic acid at a volume ratio of 95:5. Sprinkle the guar gum into the dilute acetic acid solution along the edge of a vortex while stirring at 1000 r / min. After stirring for 20 min, add the chitosan and hemicellulose, and continue stirring for another 20 min to obtain a mixture. Separately, heat a small amount of dilute acetic acid solution to 60℃, add the hydrophobic beeswax and glycerol monoacetate, and stir until completely melted. After cooling to room temperature, pour the mixture into the above mixture. Finally, add the hydrophilic silica, increase the stirring speed to 1500 r / min, and stir for 30 min. Filter through a 100-mesh sieve to obtain a uniform targeting membrane solution. The targeting layer film solution was uniformly sprayed onto the surface of the capsule core to obtain a sustained-release coated copper sulfate precursor with a "capsule core + targeting layer" structure.

[0031] S3. Core capsule + Targeting layer + Enteric coating layer By weight, 8.5 parts hydrogenated vegetable oil, 3.2 parts ethyl cellulose, and 0.3 parts lipophilic silica were weighed; methanol and chloroform were mixed in a volume ratio of 4:6 to prepare 40 parts by weight of a mixed solvent. The hydrogenated vegetable oil, ethyl cellulose, and lipophilic silica (D50 5~10 μm) were added to the mixed solvent to obtain an enteric coating solution. The enteric coating solution was uniformly sprayed onto the surface of the sustained-release coated copper sulfate precursor to obtain a sustained-release coated copper sulfate with a "core + targeting layer + enteric layer" structure.

[0032] During coating, the coating process was carried out at 30°C at a coating speed of 15 mL / min. By controlling the amount of each membrane solution, the thickness ratio of the targeting layer to the enteric layer in the sustained-release coated copper sulfate was controlled to be 10:12, and the final copper sulfate content in the sustained-release coated copper sulfate was 7.55 wt%.

[0033] Comparative Example 1 (Core only) A sodium alginate solution (5% w / w) was prepared, followed by the addition of copper sulfate pentahydrate and stirring at 400 r / min until a transparent gel-like consistency was achieved. Then, β-glucan and pregelatinized starch were added and stirring continued until homogeneous to obtain the precursor. The precursor, by weight, contained 11.8 parts copper sulfate pentahydrate, 23.6 parts sodium alginate (based on the dry weight of sodium alginate in the sodium alginate solution), 25.55 parts β-glucan, and 17.05 parts pregelatinized starch. The precursor was wet-granulated in a wet granulator. After granulation, it was dried using a fluidized bed dryer to obtain 20-mesh copper sulfate mixture particles, which served as the core. The wet granulation conditions were: stirring speed 800 r / min, shearing speed 200 r / min, and drying temperature 40℃. The copper sulfate content in the core was 9.68 wt%.

[0034] Comparative Example 2 (Core + Targeting Layer) In this comparative example, the thickness of the targeting layer is the same as in Example 1.

[0035] S1. Preparation of the core A sodium alginate solution (5% w / w) was prepared, followed by the addition of copper sulfate pentahydrate at 400 r / min with stirring until a transparent gel-like consistency was achieved. Then, β-glucan and pregelatinized starch were added and stirring continued until homogeneous to obtain the precursor. The precursor, by weight, contained 11.8 parts copper sulfate pentahydrate, 23.6 parts sodium alginate (based on the dry weight of sodium alginate in the sodium alginate solution), 25.55 parts β-glucan, and 17.05 parts pregelatinized starch. The precursor was wet-granulated in a wet granulator. After granulation, it was dried using a fluidized bed dryer to obtain 20-mesh copper sulfate mixture particles, which served as the core. The wet granulation conditions were: stirring speed 800 r / min, shearing speed 200 r / min, and drying temperature 40℃.

[0036] S2. Core capsule + Targeting layer Weigh out 3 parts by weight of guar gum, 3 parts by weight of chitosan, 0.3 parts by weight of hydrophilic silica (D50 5~10 μm), 1.6 parts by weight of hydrophobic beeswax, 1.8 parts by weight of glycerol monoacetate, and 0.3 parts by weight of hemicellulose. First, prepare a 100-part by weight dilute acetic acid solution by mixing deionized water and glacial acetic acid at a volume ratio of 95:5. Sprinkle the guar gum into the dilute acetic acid solution along the edge of a vortex while stirring at 1000 r / min. After stirring for 20 min, add the chitosan and hemicellulose, and continue stirring for another 20 min to obtain a mixture. Separately, heat a small amount of dilute acetic acid solution to 60℃, add the hydrophobic beeswax and glycerol monoacetate, and stir until completely melted. After cooling to room temperature, pour the mixture into the above mixture. Finally, add the hydrophilic silica, increase the stirring speed to 1500 r / min, and stir for 30 min. Filter through a 100-mesh sieve to obtain a uniform targeting membrane solution. The targeting layer film solution was uniformly sprayed onto the surface of the capsule core to obtain a sustained-release coated copper sulfate with a "capsule core + targeting layer" structure. The copper sulfate content in the sustained-release coated copper sulfate was 8.58 wt%.

[0037] Comparative Example 3 (Core capsule + Enteric coating) In this comparative example, the thickness of the enteric coating layer is the same as in Example 1.

[0038] S1. Preparation of the core A sodium alginate solution (5% w / w) was prepared, followed by the addition of copper sulfate pentahydrate at 400 r / min with stirring until a transparent gel-like consistency was achieved. Then, β-glucan and pregelatinized starch were added and stirring continued until homogeneous to obtain the precursor. The precursor, by weight, contained 11.8 parts copper sulfate pentahydrate, 23.6 parts sodium alginate (based on the dry weight of sodium alginate in the sodium alginate solution), 25.55 parts β-glucan, and 17.05 parts pregelatinized starch. The precursor was wet-granulated in a wet granulator. After granulation, it was dried using a fluidized bed dryer to obtain 20-mesh copper sulfate mixture particles, which served as the core. The wet granulation conditions were: stirring speed 800 r / min, shearing speed 200 r / min, and drying temperature 40℃.

[0039] S3. Core capsule + enteric coating By weight, 8.5 parts hydrogenated vegetable oil, 3.2 parts ethyl cellulose, and 0.3 parts lipophilic silica (D50 5~10 μm) were weighed; methanol and chloroform were mixed in a volume ratio of 4:6 to prepare 40 parts by weight of a mixed solvent. The hydrogenated vegetable oil, ethyl cellulose, and lipophilic silica were added to the mixed solvent to obtain an enteric coating solution. The enteric coating solution was evenly sprayed onto the surface of the capsule core to obtain a sustained-release coated copper sulfate with a "capsule core + enteric coating" structure. The copper sulfate content in the sustained-release coated copper sulfate was 8.39 wt%.

[0040] Comparative Example 4 This comparative example is basically the same as Example 1, except that in S2, the hydrophilic silica (D50 5~10μm) is replaced with an equal mass of hydrophilic silica (D50 30~40 μm).

[0041] Comparative Example 5 This comparative example is basically the same as Example 1, except that in S2, the addition of hydrophobic beeswax is omitted, and the amount of hydrophobic beeswax is made up by an equal mass of guar gum.

[0042] Comparative Example 6 This comparative example is basically the same as Example 1, except that in S2, the hydrophobic beeswax is replaced with an equal mass of solid paraffin.

[0043] Comparative Example 7 This comparative example is basically the same as Example 1, except that in S2, glyceryl monoacetate is replaced with an equal weight of propylene glycol.

[0044] [Performance Testing] 1. Gastrointestinal dissolution test Artificial gastric juice and small intestinal juice were prepared according to the requirements of the 2020 edition of the Chinese Veterinary Pharmacopoeia. The colonic digesta of weaned piglets was processed according to the relevant method of Wu Jian (Wu Jian. Effects of purified dietary fiber on the reproductive performance of sows and the intestinal microbiota of offspring [D]. Guangxi University, 2025.) and inoculated into an inoculum solution for later use; the basal culture medium of large intestinal juice was prepared according to the method of Menke et al. (MENKE KH, RAAB L, SALEWSKI A, et al. The estimation of the digestibility and metabolizable energy content of ruminant feedingstuffs from the gas production when they are incubated with rumen liquor in vitro [J]. The Journal of Agricultural Science, 1979, 93(1): 217-222.).

[0045] Artificial gastric fluid preparation procedure: Take 0.5 g of sustained-release coated copper sulfate (accurate to 0.0002 g), place it in a dissolution vessel, and add 400 mL of artificial gastric fluid using a rotating basket (instrument setup as per the 2020 edition of the Chinese Veterinary Pharmacopoeia, Part I, Method 0931). Set the temperature to 38℃ and the rotation speed to 100 r / min. After rotating for 2 h, collect the residue (filter and rinse 3 times with deionized water). Then, use an atomic absorption spectrometer (PE / AA800, USA) to determine the copper content in the residue.

[0046] Artificial small intestinal fluid operation procedure: Take out the sample that has been digested in artificial gastric fluid for 2 hours, rinse it 3 times with deionized water, and then place it in a dissolution vessel containing 400 mL of artificial small intestinal fluid. Set the temperature to 38℃ and the rotation speed to 100 r / min. After rotating for 1 hour, 2 hours, 3 hours and 4 hours, collect the residue (filter and rinse 3 times with deionized water). Use an atomic absorption spectrometer (PE / AA800, USA) to determine the copper content in the residue.

[0047] Artificial colon fluid preparation procedure: Take the sample that has been digested sequentially in artificial gastric juice for 2 h and artificial small intestinal juice for 4 h, rinse it three times with deionized water, and then transfer it to a 100 mL syringe-type glass container. Add 30 mL of culture medium and 30 mL of inoculum to the glass culture container for in vitro fermentation (this process uses nitrogen to maintain an anaerobic environment; the 3.5 cm extension tube at the tip of the syringe is covered with a silicone rubber tube, which is clamped with a water-stop clamp). Place the glass syringe in a constant temperature water shaker, set the temperature to 39℃, and the rotation speed to 80 rpb. After rotating for 1 h, 2 h, 4 h, and 6 h, collect the residue (filter and wash), and then use an atomic absorption spectrometer (PE / AA800, USA) to determine the copper content in the residue.

[0048] Table 1. Copper release rate (%) in different environments

[0049] Analysis of Table 1 shows that when only the targeting layer is coated outside the capsule core (Comparative Example 2), it rapidly dissolves (approximately 88%) after 4 hours of digestion in the small intestine, failing to achieve targeted release in the large intestine. However, when only the enteric coating is coated outside the capsule core (Comparative Example 3), it begins to release (approximately 1 / 5) after 3 hours of digestion in the small intestine, and its effective release time in the large intestine is less than 2 hours. Furthermore, in comparative examples where the key material of the targeting layer was replaced or missing: In Comparative Example 4, the increased particle size of silica led to accelerated release in the large intestine, reaching 90% after 4 hours of digestion, failing to achieve a constant release rate. In Comparative Examples 5 and 6, the absence or replacement of the key component beeswax resulted in a less robust targeting layer structure. Comparative Example 5 showed approximately 1 / 3 release after 4 hours of digestion in the small intestine, while both examples showed complete release after 4 hours of digestion in the large intestine, failing to achieve sustained and constant-rate release in the large intestine. Furthermore, Comparative Example 7 also showed that it began to release in the small intestinal fluid after 4 hours and was completely released in the large intestinal fluid after 4 hours, failing to achieve sustained release and constant rate release.

[0050] 2. Animal experiments Animal experiments were conducted using four comparative groups and one example group, both of which achieved complete release in the large intestine within 6 hours.

[0051] Seventy-two healthy weaned boars of similar weight (7.13 ± 0.27 kg) were randomly divided into three groups according to the principle of no difference in treatment, with six replicates (pens) in each group and four pigs in each replicate (pens). The three treatments were the control group, comparative group 4, and example group 1. The control group was fed a basal diet (without high-dose zinc oxide), while comparative group 4 and example group 1 were fed a basal diet plus slow-release coated copper sulfate (the uncoated copper in the basal diet was replaced by an equal amount of slow-release coated copper sulfate (500 mg / kg) from comparative group 4 and example group 1, respectively, replacing 15 mg / kg of uncoated copper in the basal diet). The total copper content in the diet of each group was ≤ 125 mg / kg. The feeding trial lasted for 14 days.

[0052] During the experiment, following the methods described by Sun et al. (SUN P, LI D, LI Z, et al. Effects of glycinin on IgE-mediated increase of mast cell numbers and histamine release in the smallintestine [J]. The Journal of Nutritional Biochemistry, 2008, 19(9): 627e33.), diarrhea scores were assessed in piglets on a daily basis (in terms of...). Figure 1As a scoring reference standard, a score of 2 or 3 was considered diarrhea, and the diarrhea rate was calculated. Simultaneously, on the afternoon of day 14, feces were collected from one piglet randomly selected from each pen via rectal stimulation, and plate counts were used to determine the number of Escherichia coli and Lactobacillus.

[0053] Table 2. Basal Diet Formulation and Nutritional Levels (Air-dried Material Basis, %)

[0054] Note: Each kilogram of feed provides 9000 IU of Vitamin A; 3 mg of Vitamin B1; 6.5 mg of Vitamin B2; 3 mg of Vitamin B6; and 1 mg of Vitamin B1. 12 Vitamins: 20 μg; Vitamin D3: 3000 IU; Vitamin E: 30 IU; Vitamin K3: 2.5 mg; Biotin: 0.1 mg; Folic acid: 0.9 mg; Pantothenic acid: 14 mg; Niacin: 40 mg; Choline: 400 mg; Iron: 100 mg; Copper: 100 mg; Manganese: 30 mg; Zinc: 80 mg; Iodine: 0.2 mg; Selenium: 0.3 mg. All nutritional levels are calculated. No antibiotics were used in the feed or on-site during this experiment.

[0055] Analysis of variance was performed on the data using SAS 9.4, and the results are expressed as mean ± standard error. The results are shown in Tables 3 and 4.

[0056] As shown in Table 3, compared with the control group, there was no significant difference in the diarrhea rate of piglets at different stages when fed the four comparative diets. P >0.05), the diarrhea rate of piglets fed the diet of Example 1 was significantly reduced on days 1-7, days 8-14, and throughout the entire course of the disease. P <0.05%. Compared with Comparative Example 4, the diet of Example 1 reduced the mortality rate of piglets on days 1-7. P = 0.061) and the rate of diarrhea throughout the course of the disease ( P The trend is 0.062.

[0057] As shown in Table 4, there were significant differences in the counts of Escherichia coli and Lactobacillus among the groups. P <0.05%. The E. coli count results showed that, compared with the control group, the E. coli count in Example 1 group was significantly reduced ( P <0.05, while the control group 4 had no significant effect on controlling the number of Escherichia coli (E. coli). P >0.05). Lactobacillus counting results showed that, compared with the control group, both Comparative Example 4 and Example 1 groups significantly increased the number of lactobacillus (>0.05). P <0.05). Furthermore, compared to Comparative Example 4, Example 1 group showed a further increase in the number of lactobacilli ( P<0.05). This result indicates that the first group of examples can regulate the intestinal microecological balance of weaned piglets by controlling the number of harmful bacteria and increasing the number of beneficial bacteria, which is beneficial for controlling diarrhea in piglets 2 weeks after weaning.

[0058] In summary, the sustained-release coated copper with stable release provided in Example 1 has a better diarrhea-relieving effect, demonstrating the importance of constant-rate release.

[0059] Table 3. Effects of different dietary treatments on diarrhea rate in piglets.

[0060] Note: Different lowercase letters in the superscript of the mean in the same column indicate significant differences. P <0.05), the superscript * indicates a significant trend compared to Example 1 group ( P <0.10).

[0061] Table 4. Effects of different dietary treatments on the content of Escherichia coli and lactic acid bacteria in rectal swabs of piglets.

[0062] Note: Different lowercase letters in the superscript of the mean in the same column indicate significant differences. P <0.05).

Claims

1. A slow-release coated copper sulfate, characterized in that, include: A copper sulfate mixture, and a targeting layer and an enteric coating layer sequentially coated on the surface of the copper sulfate mixture; The copper sulfate mixture includes copper sulfate, sodium alginate, β-glucan, and pregelatinized starch; The targeting layer includes guar gum, chitosan, hydrophilic silica, hydrophobic beeswax, glyceryl monoacetate, and hemicellulose; The enteric coating comprises hydrogenated vegetable oil, ethyl cellulose, and lipophilic silica.

2. The sustained-release coated copper sulfate as described in claim 1, characterized in that, The copper sulfate mixture comprises, by weight, 6-10 parts copper sulfate, 18-25 parts sodium alginate, 20-30 parts β-glucan and 15-20 parts pregelatinized starch.

3. The sustained-release coated copper sulfate as described in claim 1, characterized in that, By weight, the targeting layer comprises 2-3.5 parts guar gum, 2-3.5 parts chitosan, 0.2-0.4 parts hydrophilic silica, 1-2.5 parts hydrophobic beeswax, 1-2.5 parts glycerol monoacetate and 0.2-0.6 parts hemicellulose.

4. The sustained-release coated copper sulfate as described in claim 1, characterized in that, By weight, the enteric coating comprises 6-10 parts hydrogenated vegetable oil, 1-5 parts ethyl cellulose and 0.1-0.5 parts lipophilic silica.

5. The sustained-release coated copper sulfate as described in any one of claims 1 to 4, characterized in that, The sustained-release coated copper sulfate contains 8-15 wt% copper sulfate; and / or the copper sulfate mixture has a particle size of 16-25 mesh; and / or the hydrophilic silica and lipophilic silica both have a particle size of 5-10 μm.

6. The sustained-release coated copper sulfate as described in claim 1, characterized in that, The thickness ratio of the target layer to the enteric layer is (9~11):(11~13).

7. A method for preparing sustained-release coated copper sulfate as described in any one of claims 1 to 6, characterized in that, include: S1. Prepare sodium alginate solution, then add copper sulfate, β-glucan and pregelatinized starch in sequence, mix evenly, wet granulate and dry to obtain copper sulfate mixture; S2. Weigh guar gum, chitosan, hydrophilic silica, hydrophobic beeswax, glyceryl monoacetate and hemicellulose, add them to glacial acetic acid solution and mix to obtain the membrane solution for the targeting layer; S3. Weigh out hydrogenated vegetable oil, ethyl cellulose and lipophilic silica, add them to an organic solvent and mix to obtain the enteric coating membrane solution; S4. Coating the copper sulfate mixture sequentially with the membrane solution of the targeting layer and the membrane solution of the enteric layer to obtain sustained-release coated copper sulfate.

8. The preparation method according to claim 1, characterized in that, The concentration of the sodium alginate solution is 3-8 wt%; And / or, the conditions for wet granulation are: stirring speed 500~1000 r / min, shearing paddle 100~300 r / min; And / or, the drying temperature is 40~60℃; And / or, the glacial acetic acid solution is obtained by mixing glacial acetic acid and water in a volume ratio of (2~5):95; And / or, first add guar gum to a glacial acetic acid solution under stirring at 500~1000 r / min, then add chitosan and hemicellulose to obtain mixture A; separately heat the glacial acetic acid solution to 60~70℃, add hydrophobic beeswax and glyceryl monoacetate to obtain mixture B; after cooling mixture B, mix it with mixture A, and then add hydrophilic silica to obtain the membrane solution for the targeting layer; And / or, the organic solvent is obtained by mixing methanol and chloroform in a volume ratio of (3~5):6; And / or, the coating conditions are: coating is completed at 30~40℃ at a coating rate of 10~20 mL / min.

9. A feed additive, characterized in that, This includes the sustained-release coated copper sulfate as described in any one of claims 1 to 6, or the sustained-release coated copper sulfate prepared by the preparation method described in claim 7 or 8.

10. The use of the feed additive as described in claim 9 in the prevention of diarrhea in piglets.

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