A preparation method of timiconazole and application thereof

Abstract

The application discloses a preparation method of tilmicosin and application thereof, and is prepared by the following method: step (1), tilmicosin is ball milled by bran phosphoric acid to obtain material A; step (2), the material A is taken, calcium hydroxide solution is added, carbon dioxide is introduced after dehydration to obtain material B; step (3), the material B is taken, soaked in an alginic acid substance solution, dehydrated to obtain material C, further added into a coagulator solution under stirring, dehydrated to obtain material D, finally added into a dopamine solution, dried, dispersed to obtain tilmicosin. The granular material adsorbed with tilmicosin is coated by the alginic acid derivative and the polydopamine, easy to feed, and long-acting protection to poultry is realized.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of poultry medicine, in particular to a preparation method of tilmicosin and application thereof. BACKGROUND

[0002] Tilmicosin is a commonly used antibiotic for livestock and poultry, and is one of the most important respiratory disease prevention and control drugs for breeding enterprises. There are two main forms of tilmicosin: tilmicosin base and tilmicosin phosphate. Tilmicosin has a special bitter taste, and tilmicosin base is insoluble in water. Tilmicosin phosphate is easy to irritate the stomach. The prior art usually converts it into microspheres coated tilmicosin base for slow release absorption in the gastrointestinal tract. Poultry is prone to respiratory infectious diseases, and it can assist digestion through the gizzard, which can easily decompose the microspheres of tilmicosin base into decarboxylated tylosin, resulting in reduced antibacterial activity.

[0003] CN107383132A discloses a water-soluble tilmicosin phosphate and a preparation method and application thereof. During preparation, a substance containing phosphate is added to water and dissolved, heated to 50-70℃, then tilmicosin is added and dissolved, followed by adjusting the pH value to 5.0-8.0 with an alkaline substance, keeping for 15-30min, then adding a solid adsorbent, stirring, and then filtering, concentrating and drying. The prepared water-soluble tilmicosin phosphate is used for preventing and treating respiratory infections of animal breeds and pets. CN112516085B discloses a tilmicosin solution and a preparation method and use method thereof. The tilmicosin solution comprises the following raw materials in weight percentage: 10-50% tilmicosin, 4-10% mixed agent, 1-3% solubilizer, 8-15% emulsifier, 2-5% co-emulsifier, 1-3% flavoring agent, 0.5-2% taste blocking agent, 8-20% oil phase material and the balance of water. The emulsifier is composed of a natural emulsifier and a non-ionic surfactant. The above-mentioned solutions cannot solve the problem of slow release of tilmicosin for poultry medicine. SUMMARY

[0004] In order to solve the above problems, the present application provides a preparation method of tilmicosin and application thereof, which realizes long-acting protection for poultry by polymer coating of the particles adsorbing tilmicosin.

[0005] To achieve the above-mentioned purposes, the technical scheme of the present application is as follows:

[0006] A preparation method of tilmicosin, comprising the following steps:

[0007] Step (1): 10-20 parts of bran and 1 part of tilmicosin phosphate are mixed and then added to water, followed by ball milling, and the material A is obtained.

[0008] Step (2): Take 10 to 20 parts of material A, add 1 part of saturated calcium hydroxide solution, stir, dehydrate to obtain a cake, and pass carbon dioxide into the cake to obtain material B;

[0009] Step (3): Take 10 to 20 parts of material B, soak them in a 5% to 10% mass concentration of an alginic acid solution, dehydrate them to obtain material C, add material C to a 0.5% to 1% mass concentration of a coagulant solution under stirring, and then dehydrate to obtain material D, add material D to a 0.5% to 1.5% mass concentration of dopamine solution, introduce air, adjust the pH to 8.5, react for 15 hours, dehydrate, dry, and disperse to obtain tilmicosin.

[0010] Preferably, in step (1), during the ball milling process, the mass of water is 1 to 2 times that of the bran; and the average particle size of the material A obtained after ball milling is 10 μm to 50 μm.

[0011] Preferably, in step (2), the stirring conditions are 300 r / min to 500 r / min, and the stirring time is 30 min to 60 min.

[0012] Preferably, in step (2), the moisture content of the cake is 15% to 25%.

[0013] Preferably, in step (3), the alginic acid substance includes one or more of alginic acid, sodium alginate, and potassium alginate; and the coagulant is calcium chloride or calcium lactate.

[0014] Preferably, in step (3), the stirring condition is 800 r / min to 1000 r / min; and the drying method is baking at 60° C. to 80° C.

[0015] Preferably, in step (3), the water content of tilmicosin is less than 5% by weight.

[0016] Preferably, in step (3), material D is added to a dopamine solution having a mass concentration of 0.5% to 1.5%, the pH is adjusted to 8.5, air is introduced, and the reaction is carried out for 15 to 24 hours, followed by dehydration, drying, and dispersion to obtain tilmicosin. This is to ensure the auto-oxidative polymerization reaction of dopamine.

[0017] This proposal also proposes a tilmicosin prepared by the above-mentioned preparation method of tilmicosin.

[0018] The present invention relates to the use of tilmicosin in poultry.

[0019] Compared with existing technologies, the advantages of this solution are:

[0020] 1. This solution can achieve a good sustained-release effect of tilmicosin through the action of a multilayer film, and better adapt to the digestion mode of poultry. This solution uses bran as a substrate, and through ball milling, tilmicosin phosphate is adsorbed on the surface of the bran. At the same time, bran has the characteristics of a porous surface and a large specific surface area, which can provide a large number of active adsorption points. Step (2) allows tilmicosin phosphate to react to tilmicosin base, and at the same time generates calcium phosphate, which can fill the porous surface of the bran. Under the action of carbon dioxide, the residual calcium hydroxide reacts to form a calcium carbonate film, which is coated on the surface of the bran particles. Furthermore, in step (3), after material B is soaked in an alginic acid solution, a thin film of the alginic acid solution remains on the surface of material C. After material C is added with a coagulant solution, a polymer network of alginic acid is formed on the surface under stirring conditions, namely material D. After material D is soaked in a 0.5% to 5% dopamine solution, dopamine monomers remain on the surface, and self-oxidize to form a film during the subsequent drying process to form a polydopamine film.

[0021] 2. This approach uses bran as a base material and can be incorporated into feed as needed or used directly as feed. Poultry digestion requires the aid of their gizzard to grind food. This approach fully incorporates tilmicosin with bran. Gizzard grinding partially disrupts the polymer film coating tilmicosin, allowing it to be gradually released during digestion, improving the drug's long-lasting efficacy. DETAILED DESCRIPTION

[0022] The following describes the implementation of the present invention using specific embodiments. Those skilled in the art will readily understand the other advantages and benefits of the present invention from the disclosure herein. Obviously, the embodiments described are only a portion of the present invention, not all of it. All other embodiments derived by persons of ordinary skill in the art based on the embodiments of the present invention without inventive effort are intended to fall within the scope of protection of the present invention.

[0023] Example 1

[0024] A method for preparing tilmicosin comprises the following steps:

[0025] Step (1): 15 parts of bran and 1 part of tilmicosin phosphate are mixed by weight and added to 15 parts of water, followed by ball milling and unloading to obtain material A with an average particle size of 30 μm; the effects of ball milling are as follows: 1. the bran may agglomerate in water, and ball milling can fully infiltrate it; 2. the bran is broken up, increasing the specific surface area and the active adsorption sites; the bran is 50% wheat bran and 50% rice bran;

[0026] Step (2): taking 15 parts of material A, adding 1 part of saturated calcium hydroxide solution, 400 r / min, stirring for 30 minutes, filtering and dehydrating to obtain a cake with a water percentage of 20%, and introducing carbon dioxide into the cake to obtain material B; the role of calcium hydroxide is to convert tilmicosin phosphate into tilmicosin base, and at the same time generate calcium phosphate to block the bran micropores. Under the action of carbon dioxide, a calcium carbonate film is generated to coat the bran. Under the condition of gastric acid, part of the calcium carbonate film decomposes, and some of the formed carbon dioxide microbubbles fail to overflow in time, which may be able to block part of the reaction, allowing the tilmicosin base to enter the intestine for absorption;

[0027] Step (3): Take 15 parts of material B, soak them in a sodium alginate solution with a mass concentration of 8%, filter and dehydrate to obtain material C, add material C to a coagulant solution with a mass concentration of 0.8% under stirring conditions of 1000r / min, and then dehydrate to obtain material D, add material D to a dopamine solution with a mass concentration of 0.8%, introduce air, adjust the pH to 8.5, react for 15h, dehydrate, dry at 70℃, and disperse to obtain tilmicol with a water content of 3.2%. star; the concentration of the coagulant solution should not be too high, and it needs to be combined with high-speed stirring, otherwise the calcium alginate polymer generated on the surface of material C will easily wrap a large amount of material C into a ball, and the surface of material C inside the ball is not protected by the calcium alginate polymer, which is easy to quickly release tilmicosin under gastric acid conditions, causing irritation to the stomach; further, the dopamine remaining on the surface of material D will self-oxidize to form a film to form polydopamine during the drying process. Polydopamine is not easily decomposed in the digestive system and is a good protective layer, which is conducive to the sustained release of tilmicosin.

[0028] Example 2

[0029] Step (1): by weight, 18 parts of bran and 1 part of tilmicosin phosphate were mixed and added to 20 parts of water, followed by ball milling and unloading to obtain material A with an average particle size of 45 μm; the bran was 50% wheat bran and 50% rice bran;

[0030] Step (2): Take 18 parts of material A, add 1 part of saturated calcium hydroxide solution, stir at 500 r / min for 60 min, filter and dehydrate to obtain a cake with a water content of 23%, and pass carbon dioxide into the cake to obtain material B;

[0031] Step (3): Take 12 parts of material B, soak them in a potassium alginate solution with a mass concentration of 5%, dehydrate them to obtain material C, add material C to a calcium lactate solution with a mass concentration of 0.7% under stirring at 900 r / min, and then dehydrate to obtain material D; add material D to a dopamine solution with a mass concentration of 1.3%, let air flow into it, adjust the pH to 8.5, react for 15 hours, dehydrate, dry at 75°C, and disperse to obtain tilmicosin with a water content of 2.6%.

[0032] Comparative Example 1

[0033] A preparation method of tilmicosin, comprising the following steps:

[0034] Step (1): 15 parts of bran and 1 part of tilmicosin phosphate are mixed and then added to 15 parts of water, to obtain material A; the bran is 50% wheat bran and 50% rice bran;

[0035] Step (2): 15 parts of material A are taken, 1 part of saturated calcium hydroxide solution is added, stirring at 400 r / min for 30 min, filtration and dehydration, to obtain material cake with a water content of 18%, carbon dioxide is introduced into the material cake to obtain material B;

[0036] Step (3): 10-20 parts of material B are soaked in a 8% sodium alginate solution, filtration and dehydration are performed, to obtain material C, which is added to a 0.8% coagulant solution under the condition of stirring at 1000 r / min, followed by dehydration, to obtain material D, which is added to a 0.8% dopamine solution, air is introduced, the pH is adjusted to 8.5, and after reaction for 15 h, dehydration is performed, 70°C drying is performed, and dispersion is performed, to obtain tilmicosin with a water content of 3.6%.

[0037] Comparative Example 2

[0038] A preparation method of tilmicosin, comprising the following steps:

[0039] Step (1): 15 parts of bran and 1 part of tilmicosin phosphate are mixed and then added to 15 parts of water, followed by ball milling and unloading, to obtain material A with an average particle size of 30 μm; the bran is 50% wheat bran and 50% rice bran;

[0040] Step (2): 15 parts of material A are taken, 1 part of saturated calcium hydroxide solution is added, stirring at 400 r / min for 30 min, filtration and dehydration are performed, to obtain material cake with a water content of 18%, carbon dioxide is introduced into the material cake to obtain material B;

[0041] Comparative Example 3

[0042] A preparation method of tilmicosin, comprising the following steps:

[0043] Step (1): 15 parts of bran and 1 part of tilmicosin phosphate are mixed and then added to 15 parts of water, followed by ball milling and unloading, to obtain material A with an average particle size of 30 μm; the bran is 50% wheat bran and 50% rice bran;

[0044] Step (2): Take 15 parts of material A, add 1 part of saturated calcium hydroxide solution, stir at 400 r / min for 30 minutes, filter and dehydrate to obtain material B with a water percentage of 20%;

[0045] Step (3): Take 15 parts of material B, soak them in a sodium alginate solution with a mass concentration of 8%, filter and dehydrate to obtain material C, add material C to a coagulant solution with a mass concentration of 0.8% under stirring at 1000 r / min, and then dehydrate to obtain material D, add material D to a dopamine solution with a mass concentration of 0.8%, introduce air, adjust the pH to 8.5, react for 15 hours, dehydrate, dry at 70°C, and disperse to obtain tilmicosin with a water content of 3.2%.

[0046] Comparative Example 4

[0047] A method for preparing tilmicosin comprises the following steps:

[0048] Step (1): by weight, 15 parts of bran and 1 part of tilmicosin phosphate were mixed and added to 15 parts of water, followed by ball milling and unloading to obtain material A with an average particle size of 30 μm; the bran was 50% wheat bran and 50% rice bran;

[0049] Step (2): Take 15 parts of material A, add 1 part of saturated calcium hydroxide solution, stir at 400 r / min for 30 minutes, filter and dehydrate to obtain a cake with a water percentage of 20%, and pass carbon dioxide into the cake to obtain material B;

[0050] Step (3): Take 15 parts of material B, soak them in a sodium alginate solution with a mass concentration of 8%, filter and dehydrate to obtain material C, add material C to a coagulant solution with a mass concentration of 2.5% under stirring at 200 r / min, and then dehydrate to obtain material D, add material D to a dopamine solution with a mass concentration of 0.8%, introduce air, adjust the pH to 8.5, react for 15 hours, dehydrate, dry at 70°C, and disperse to obtain tilmicosin with a water content of 2.8%.

[0051] Comparative Example 5

[0052] A method for preparing tilmicosin comprises the following steps:

[0053] Step (1): by weight, 15 parts of bran and 1 part of tilmicosin phosphate were mixed and added to 15 parts of water, followed by ball milling and unloading to obtain material A with an average particle size of 30 μm; the bran was 50% wheat bran and 50% rice bran;

[0054] Step (2): Take 15 parts of material A, add 1 part of saturated calcium hydroxide solution, stir at 400 r / min for 30 minutes, filter and dehydrate to obtain a cake with a water percentage of 20%, and pass carbon dioxide into the cake to obtain material B;

[0055] Step (3): Take 10 to 20 parts of material B, soak them in a sodium alginate solution with a mass concentration of 8%, filter and dehydrate to obtain material C, add material C to a coagulant solution with a mass concentration of 0.8% under stirring at 1000 r / min, introduce air, adjust the pH to 8.5, react for 15 hours, dehydrate, dry at 70°C, and disperse to obtain tilmicosin with a water content of 1.8%.

[0056] Effect test:

[0057] Adsorption amount refers to the mass of tilmicosin phosphate adsorbed per unit mass of bran after step (1); activity amount refers to the mass of the actual active substance in tilmicosin per unit mass after step (3), i.e., the mass of tilmicosin base.

[0058] 75 chickens with respiratory disease and 75 healthy chickens of similar size were randomly selected and divided into 15 groups for mixed breeding, each containing 5 diseased chickens and 5 healthy chickens, numbered 1 to 15. Group 1 served as a blank control group and was fed a standard feed daily. In Groups 2 to 15, the even-numbered groups were fed a standard feed supplemented with 50% tilmicosin, while the odd-numbered groups were fed 100% tilmicosin daily. The tilmicosin was prepared according to Examples 1-2 and Comparative Examples 1-5, respectively. The test results after 15 days of feeding are shown in Table 1.

[0059] Table 1

[0060]

[0061] From the results in Table 1, it can be seen that Example 1-2 has obvious advantages, which is due to the fact that the tilmicosin prepared in this solution has multi-layer protection, which slows down the release of tilmicosin and prolongs the protection time.

[0062] The difference between Comparative Example 1 and Example 1 is that the bran is not ball-milled, which results in insufficient adsorption of tilmicosin phosphate and is easily washed away during the later dehydration process, resulting in poor effect; the difference between Comparative Example 2 and Example 1 is that calcium hydroxide is not added to convert tilmicosin phosphate into tilmicosin base, and tilmicosin is also easily lost during the later dehydration process; the difference between Comparative Example 3 and Example 1 is that carbon dioxide is not introduced, which causes the residual calcium hydroxide to react with the subsequent sodium alginate prematurely, resulting in agglomeration and poor sustained release effect; the difference between Comparative Example 4 and Example 1 is that the stirring rate in step (3) is too slow and the coagulant concentration is too high, resulting in agglomeration and poor sustained release effect; the difference between Comparative Example 5 and Example 1 is that no polydopamine film is formed, the sustained release layer has insufficient corrosion resistance, and the sustained release effect is poor.

Claims

1. A method for preparing tilmicosin, characterized in that: The following steps are involved: Step (1): by weight, 10 to 20 parts of bran and 1 part of tilmicosin phosphate are mixed and added to water, followed by ball milling and unloading to obtain material A; the mass of water is 1 to 2 times that of the bran; the average particle size of the material A obtained after ball milling is 10 μm to 50 μm; Step (2): Take 10 to 20 parts of material A, add 1 part of saturated calcium hydroxide solution, stir, dehydrate to obtain a cake, and pass carbon dioxide into the cake to obtain material B; Step (3): taking 10 to 20 parts of material B, soaking them fully in a solution of an alginic acid substance having a mass concentration of 5% to 10%, dehydrating them to obtain material C, adding material C to a coagulant solution having a mass concentration of 0.5% to 1% under stirring conditions, and then dehydrating them to obtain material D, adding material D to a dopamine solution having a mass concentration of 0.5% to 1.5%, adjusting the pH to 8.5, introducing air, reacting for 15 hours to 24 hours, dehydrating, drying, and dispersing them to obtain tilmicosin; The alginic acid substance includes one or more of alginic acid, sodium alginate, and potassium alginate; and the coagulant is calcium chloride or calcium lactate.

2. The method for preparing tilmicosin according to claim 1, wherein In step (2), the stirring condition is 300 r / min~500 r / min, and the stirring time is 30min~60min.

3. The method for preparing tilmicosin according to claim 1, wherein In step (2), the moisture content of the cake is 15% to 25%.

4. The method for preparing tilmicosin according to claim 1, wherein In step (3), the stirring condition is 800 r / min~1000 r / min; the drying method is baking at 60°C~80°C.

5. The method for preparing tilmicosin according to claim 1, wherein In step (3), the water content of tilmicosin is less than 5% by weight.

6. Tilmicosin prepared by the method for preparing Tilmicosin according to any one of claims 1 to 5.

7. The tilmicosin according to claim 6 is used for poultry.

Images