A water-soluble tilmicosin premix and its preparation method

Abstract

This invention belongs to the field of veterinary drug formulation technology, specifically relating to a water-soluble tilmicosin premix and its preparation method. Its composition includes the following raw materials: tilmicosin phosphate, citric acid, tartaric acid, polyvinylpyrrolidone K30, sulfobutyl-β-cyclodextrin, citrate buffer pair, sodium gluconate, tetrasodium diacetate of glutamate, alkylated hydroxypropyl methylcellulose, binuclear seeds, mannitol, microcapsule NaHCO3, fumed silica, and lecithin. This invention first uses citric acid, tartaric acid, and PVP to co-amorphize and spray-dry tilmicosin phosphate to prepare a masterbatch, improving solubility and reducing recrystallization tendency; then, it sprays an inner layer containing sulfobutyl-β-cyclodextrin, etc., followed by a GLDA chelating layer, a modified cellulose hydrophilic membrane, a binuclear carrier, mannitol isolation, microcapsule NaHCO3, an outer layer of lecithin, and fumed silica to optimize dissolution and stability.

Description

Technical Field

[0001] This invention belongs to the field of veterinary drug formulation technology, specifically relating to a water-soluble tilmicosin premix and its preparation method. Background Technology

[0002] Tilmicosin, a 16-membered macrolide antibiotic, is widely used clinically to prevent and treat respiratory infections in ruminants, pigs, and poultry. Common formulations include injections, feed premixes, and water-soluble powders. Injection administration suffers from low individual compliance and high costs associated with group administration; feed premixes are efficacy-dependent, and insufficient administration can occur when animals are anorexic; while water administration offers rapid onset of action and good group coverage, it places higher demands on the formulation's solubility in aqueous phase, dissolution kinetics, clarity, hard water compatibility, pipeline compatibility, and stability.

[0003] The technological development of water-based tilmicosin formulations still faces several common challenges. First, there is the contradiction between solubility and clarity. Although tilmicosin is often used in salt form, its dissolution rate and final clarity are significantly affected by pH and ionic strength. Some existing formulations promote dissolution through strong acidification or the use of large amounts of surfactants, but this easily leads to decreased palatability, increased foaming, turbidity, and even water line residue and nozzle clogging. In hard water or in the presence of minerals such as bentonite, zeolite, and calcium phosphate, drug molecules are prone to electrostatic adsorption, ion bridging, or co-precipitation, resulting in decreased free drug concentration and increased apparent turbidity. Second, traditional tilmicosin formulations have poor dissolution stability. As a macrolide compound, tilmicosin may hydrolyze or recrystallize under high temperature and humidity conditions. Some soluble powders show delayed dissolution and decreased clarity after long-term storage or exposure to thermal cycling, affecting the reliability of administration and expected efficacy. In addition, traditional fine powder or simple physical mixture-type powders are prone to moisture absorption and clumping, have poor flowability, and are prone to separation and precipitation after transportation and vibration. This can lead to uneven concentrations in secondary preparations and non-compliance with batch content uniformity requirements. At the same time, there are operational safety risks caused by dust exposure. Summary of the Invention

[0004] This invention addresses the shortcomings of existing technologies by providing a water-soluble tilmicosin premix and its preparation method. To solve the problems of easy adsorption and deposition in hard water / mineral environments, slow onset of action, turbidity, and poor transport stability of existing water-soluble tilmicosin, this invention first uses citric acid and tartaric acid with PVP to co-amorphize the drug, improving its initial dissolution rate and heat and moisture stability. An inner layer is sprayed with sulfobutyl-β-cyclodextrin, citrate buffer, and sodium gluconate to effectively reduce the adsorption of the drug with minerals such as bentonite, zeolite, and calcium phosphate, and to stabilize the pH of the system. A thin layer is then sprayed with tetrasodium diacetate of glutamate to provide short-term continuous chelation and inhibit the formation of turbidity in the later stages. An outer layer uses amphiphilic cellulose and lecithin to promote instantaneous wetting and inhibit drug recrystallization. A bicore carrier is constructed using mannitol and anhydrous glucose, combined with a segmented spraying process to achieve a uniform, anti-segregation, and stable film structure.

[0005] The technical effects described in this invention are achieved through the following technical solution: a water-soluble tilmicosin premix, comprising the following raw materials: tilmicosin phosphate, citric acid, tartaric acid, polyvinylpyrrolidone K30, sulfobutyl-β-cyclodextrin, citrate buffer pair, sodium gluconate, tetrasodium diacetate of glutamate, alkylated hydroxypropyl methylcellulose, binuclear seeds, mannitol, microcapsule NaHCO3, fumed silica, and lecithin.

[0006] Furthermore, the particle size distribution D of the tilmicosin phosphate 90 The particle size should be 10–20 μm, meaning that when the cumulative volume fraction in the particle size distribution reaches 90%, the corresponding particle size needs to be 10–20 μm.

[0007] Furthermore, the citrate buffer pair is composed of citric acid and sodium citrate in a 1:1 mass ratio;

[0008] Furthermore, the binucleate seed is prepared by mixing mannitol and anhydrous glucose in a mass ratio of 8:2;

[0009] More preferably, the particle size distribution D of the mannitol is... 50 The particle size should be 150–250 μm, meaning that when the cumulative volume fraction in the particle size distribution reaches 50%, the corresponding particle size needs to be 150–250 μm.

[0010] More preferably, the particle size distribution D of the anhydrous glucose is... 50 The thickness is 90–140 μm;

[0011] Furthermore, the specific preparation process of the alkylated hydroxypropyl methylcellulose is as follows:

[0012] 1. Hydroxypropyl methylcellulose was added to an 80wt% isopropanol solution and stirred until homogeneous to obtain an 8-12wt% homogeneous slurry. NaOH solution was slowly added to adjust the pH to 11.5-12.5. The mixture was stirred at 30-40°C for 30 min, then heated to 45-55°C. Lauryl glycidyl ether was added dropwise, and the mixture was stirred continuously at 300 rpm and kept at this temperature for 2-4 h. The mixture was then cooled to 35°C, and the pH was adjusted to 7-7.5 with glacial acetic acid. The mixture was filtered and washed with 70wt% isopropanol solution until the residual epoxy value test was negative. The mixture was then vacuum dried at 50-55°C until the LOD was ≤5% to obtain alkylated hydroxypropyl methylcellulose.

[0013] Furthermore, the ratio of lauryl glycidyl ether to hydroxypropyl methylcellulose is 0.6–0.8 mL: 10 g;

[0014] Furthermore, the specific preparation process of the microcapsule NaHCO3 is as follows:

[0015] 1) Dry NaHCO3 under vacuum at 45-50°C for 2-4 hours, cool to 35-40°C to make a bed material; heat glyceryl stearate to 90°C to melt, add 0.5-1% lecithin and stir evenly, spray it onto the surface of the bed material, with inlet air at 60-70°C and outlet air at 35-40°C, spraying rate at 8-15 g / min·kg bed material, atomized air at 0.8-1.2 bar, wall material weight gain of 10-15%, fluidize at room temperature for 5-10 min, and screen through a 40-mesh sieve to obtain microcapsule NaHCO3;

[0016] Another aspect of the present invention is to provide a method for preparing a water-soluble tilmicosin premix, specifically comprising the following steps:

[0017] (1): Dissolve polyvinylpyrrolidone K30, citric acid and tartaric acid in deionized water at 45-50℃, then add tilmicosin phosphate, stir to disperse evenly, spray dry to obtain master powder;

[0018] (2): Dissolve sulfobutyl-β-cyclodextrin in deionized water at 40-50℃, add citric acid buffer to adjust the pH to 6.3-6.5, then add sodium gluconate and dissolve evenly to obtain a buffer softening synergistic solution;

[0019] (3): Dissolve tetrasodium glutamate diacetate in deionized water to obtain a 20-25 wt% GLDA aqueous solution; dissolve alkylated hydroxypropyl methylcellulose in deionized water at 80-90℃ and cool to room temperature to obtain a 6-8 wt% cellulose solution; spray the buffer softening synergistic solution from step (2) onto the binuclear seeds, and simultaneously feed the mother powder from step (1) at a feeding rate of 12-16 g / min·kg, with a target deposition of 300 g / kg of bed material; then, under the same temperature and control, spray the GLDA aqueous solution sequentially at a spray volume of 20 g / kg of bed material; and the cellulose aqueous solution at a spray volume of 150-180 g / kg of bed material.

[0020] (4): After completing the spraying treatment in step (3), continue the spraying treatment under the same temperature and control. First, spray a 15wt% mannitol aqueous solution with a spray volume of 35-45g / kg of bed material; then feed microcapsule NaHCO3 quantitatively with a feeding volume of 5-10g / kg of bed material; finally, spray a 4-6wt% lecithin solution with a spray volume of 30-50g / kg of bed material; screen through a 40-mesh sieve, add 0.5-1% of fumed silica by weight of the finished product, dry mix evenly, seal with nitrogen, and obtain water-soluble tilmicosin premix.

[0021] Further, in step (1), the ratio of the amounts of polyvinylpyrrolidone, tilmicosin phosphate, citric acid, tartaric acid and deionized water is 0.3-0.5g:1-1.2g:0.06-0.08g:0.02-0.05g:100mL;

[0022] Further, in step (1), the spray drying parameters are: air inlet 140-150°C, air outlet 75-85°C, and atomized air 2-2.5 bar;

[0023] Further, in step (2), the ratio of the amount of sulfobutyl-β-cyclodextrin, sodium gluconate and deionized water is 2-3g:0.8-1.2g:10mL;

[0024] Further, in step (3), the spraying parameters of the buffer softening synergistic liquid are: air inlet 60-75℃, air outlet 44-48℃, atomized air 1.6-2 bar; liquid feed 10-20 g / min·kg, spray volume 300-400 g / kg bed material;

[0025] Furthermore, in step (3), when the cellulose aqueous solution is sprayed, the liquid feed rate is adjusted to 5-10 g / min·kg bed material.

[0026] The beneficial effects of this invention are as follows:

[0027] Compared to existing technologies, this invention first employs citric acid and tartaric acid with polyvinylpyrrolidone to co-amorphize tilmicosin phosphate, combined with spray drying, to transform the drug into a glassy state with higher energy levels but a restricted structure. This improves the drug's apparent solubility and reduces its recrystallization tendency under humid and hot conditions, providing a stable starting material for subsequent aqueous diffusion and solution clarification. The resulting masterbatch is rich in polar groups and PVP segments, accelerating the hydration rate without introducing insoluble phases or strong complexing sites, which is beneficial for synergistic effects with subsequent aqueous solubilization and buffering systems. Then, a synergistic solution containing sulfobutyl-β-cyclodextrin, sodium citrate buffer, and sodium gluconate is preferentially sprayed as the inner layer. In this system, cyclodextrin and tilmicosin form a host-guest inclusion structure, effectively reducing hydrophobic interactions and the exposed area of ​​potential points in the aqueous phase, thereby inhibiting electrostatic adsorption and ion bridging with bentonite, zeolite, and calcium-containing inorganic salt surfaces. The buffer system stabilizes the pH of the particle surface microenvironment within a weakly acidic range, which is more conducive to the dissolution of this salt-type drug; sodium gluconate can react with Ca in the initial stage of water introduction. 2+ / Mg 2+ Mild complexation occurs, reducing the interference of water hardness ions on drug dissociation and diffusion, which helps to obtain a clear or low-turbidity solution.

[0028] To mitigate the effects of hardness ions entering the drinking water system and gastrointestinal environment over time, a thin spray of tetrasodium glutamate diacetate (GLDA) is applied to form a slow-release chelating layer, maintaining effective calcium absorption even shortly after water introduction. 2+ / Mg 2+ The capture capacity is enhanced, reducing subsequent sedimentation and secondary turbidity. A low-dose amphiphilic modified cellulose (alkylated hydroxypropyl methylcellulose) forms a hydrophilic film layer on the outer surface, significantly reducing the water contact angle, increasing wetting and disaggregation rates, and inhibiting secondary crystallization and re-adsorption of the drug on the particle surface. This kinetically shortens the time required to achieve stable clarity while maintaining compatibility with the inner functional components without adverse reactions. Furthermore, a dual-core carrier of mannitol and anhydrous glucose is selected, and particle size distribution is controlled to make the crossing probability and coating uniformity of the two types of seeds in the spraying area easier to manage, reducing leaching and segregation during transportation and secondary packaging. To avoid acid-base interactions during storage, a thin layer of mannitol is added between the functional inner layer and sodium bicarbonate as a barrier; the microcapsule sodium bicarbonate layer can rapidly release a small amount of CO2 after water introduction, accelerating pore wetting and disaggregation without changing the system's pH or clarity. The outermost layer of low-content lecithin further reduces surface tension and improves compatibility with drinking water system materials, reducing the risk of wall adhesion and nozzle clogging; the end dry-mixed fumed silica improves powder flowability and reduces bridging and agglomeration tendency. Attached Figure Description

[0029] Figure 1Figure 1 shows the dissolution test results of the tilmicosin premixes prepared in Example 1 and Comparative Examples 1-4 in 400 ppm hard water medium.

[0030] Figure 2 Figure 1 shows the dissolution test results of the tilmicosin premixes prepared in Example 1 and Comparative Examples 1-4 in 800 ppm hard water medium.

[0031] Figure 3 Figure 1 shows the dissolution test results of the tilmicosin premixes prepared for Example 1 and Comparative Examples 1-4 in 400 ppm mineral hard water medium.

[0032] Figure 4 The graph shows the change in water content during the stability test of the tilmicosin premixes prepared in Example 1 and Comparative Examples 1-4.

[0033] Figure 5 The graph shows the turbidity change over 2 minutes during the stability test of the tilmicosin premixes prepared in Example 1 and Comparative Examples 1-4.

[0034] Figure 6 The graph shows the turbidity change over 5 minutes during the stability test of the tilmicosin premixes prepared in Example 1 and Comparative Examples 1-4.

[0035] Figure 7 pH change graphs during stability testing of tilmicosin premixes prepared in Example 1 and Comparative Examples 1-4;

[0036] Figure 8 The particle size distribution curve of the tilmicosin premix prepared in Example 1. Detailed Implementation

[0037] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Unless otherwise specified, the raw materials involved in the present invention are all purchased through conventional commercial channels. Experimental methods without specific conditions are conventional methods and conditions well known in the art, or according to the conditions recommended by the instrument manufacturer.

[0038] Example 1: A water-soluble tilmicosin premix, comprising the following raw materials: tilmicosin phosphate, citric acid, tartaric acid, polyvinylpyrrolidone K30, sulfobutyl-β-cyclodextrin, citrate buffer pair, sodium gluconate, tetrasodium diacetate of glutamate, alkylated hydroxypropyl methylcellulose, binuclear seeds, mannitol, microcapsule NaHCO3, fumed silica, and lecithin.

[0039] The citric acid buffer pair is composed of citric acid and sodium citrate in a 1:1 mass ratio;

[0040] The dual-core seed is prepared by mixing mannitol and anhydrous glucose in a mass ratio of 8:2.

[0041] The specific preparation process of the alkylated hydroxypropyl methylcellulose is as follows:

[0042] 1. Add 100g of hydroxypropyl methylcellulose to 1000mL of 80wt% isopropanol solution and stir until homogeneous to obtain a 10wt% homogeneous slurry. Slowly add NaOH solution to adjust the pH to 12, stir at 35°C for 30min, raise the temperature to 50°C, add 7mL of lauryl glycidyl ether dropwise, stir continuously at 300rpm and keep warm for 3h, cool to 35°C, adjust the pH to 7.2 with glacial acetic acid, filter, wash with 70wt% isopropanol solution until the residual epoxy value test is negative, and vacuum dry at 52°C until LOD ≤ 5% to obtain alkylated hydroxypropyl methylcellulose.

[0043] The specific preparation process of the microcapsule NaHCO3 is as follows:

[0044] 1) Dry 100g of NaHCO3 under vacuum at 48°C for 3h, cool to 38°C and use as bed material; heat 12g of glyceryl stearate to 90°C to melt, add 0.096g of lecithin and stir evenly, spray on the surface of bed material, with air inlet temperature of 65°C, air outlet temperature of 38°C, spraying rate of 10g / min·kg bed material, atomized air of 1 bar, wall material weight gain of 12%, fluidize at room temperature for 8min, and screen through a 40-mesh sieve to obtain microcapsule NaHCO3;

[0045] The preparation of the water-soluble tilmicosin premix specifically includes the following steps:

[0046] (1): Dissolve 4g of polyvinylpyrrolidone K30, 0.7g of citric acid and 0.3g of tartaric acid in 1000mL of deionized water at 48℃, then add 11g of tilmicosin phosphate, stir to disperse evenly, spray dry, with air inlet at 145℃, air outlet at 80℃, and atomized air at 2.5bar to obtain the master powder;

[0047] (2): Dissolve 25g of sulfobutyl-β-cyclodextrin in 100mL of deionized water at 45℃, add citric acid buffer to adjust the pH to 6.4, then add 10g of sodium gluconate and dissolve evenly to obtain a buffer softening synergistic solution.

[0048] (3): Dissolve tetrasodium glutamate diacetate in deionized water to obtain a 25wt% GLDA aqueous solution; dissolve alkylated hydroxypropyl methylcellulose in deionized water at 85℃ and cool to room temperature to obtain a 7wt% cellulose solution; spray the buffer softening synergistic liquid from step (2) onto 100g of binuclear seeds, with an air inlet temperature of 70℃ and an outlet temperature of 46℃, and atomized air at 2 bar; feed liquid at 15g / min·kg, spray liquid at 350g / kg bed material, and simultaneously feed the mother powder from step (1) at a feeding rate of 15g / min·kg, with a target deposition of 300g / kg bed material; spray GLDA aqueous solution sequentially under the same temperature and control, with a spray liquid at 20g / kg bed material; and cellulose aqueous solution, adjusting the liquid feed rate to 8g / min·kg bed material and the spray liquid at 160g / kg bed material;

[0049] (4): After completing the spraying treatment in step (3), continue the spraying treatment under the same temperature and control. First, spray 15wt% mannitol aqueous solution, with a spraying amount of 40g / kg bed material; then quantitatively feed microcapsule NaHCO3, with a feeding amount of 8g / kg bed material; finally, spray 5wt% lecithin solution, with a spraying amount of 40g / kg bed material; screen through a 40-mesh sieve, add 0.8% fumed silica by weight of the finished product, dry mix evenly, seal with nitrogen, and obtain water-soluble tilmicosin premix.

[0050] Example 2: A water-soluble tilmicosin premix, comprising the following raw materials: tilmicosin phosphate, citric acid, tartaric acid, polyvinylpyrrolidone K30, sulfobutyl-β-cyclodextrin, citrate buffer pair, sodium gluconate, tetrasodium diacetate of glutamate, alkylated hydroxypropyl methylcellulose, binuclear seeds, mannitol, microcapsule NaHCO3, fumed silica, and lecithin.

[0051] The citric acid buffer pair is composed of citric acid and sodium citrate in a 1:1 mass ratio;

[0052] The dual-core seed is prepared by mixing mannitol and anhydrous glucose in a mass ratio of 8:2.

[0053] The specific preparation process of the alkylated hydroxypropyl methylcellulose is as follows:

[0054] 1. Add 80g of hydroxypropyl methylcellulose to 1000mL of 80wt% isopropanol solution and stir until homogeneous to obtain 8wt% homogeneous slurry; slowly add NaOH solution to adjust the pH to 11.5, stir at 30°C for 30min, raise the temperature to 45°C, add 4.8mL of lauryl glycidyl ether dropwise, stir continuously at 300rpm and keep warm for 2h, cool to 35°C, adjust the pH to 7 with glacial acetic acid, filter, wash with 70wt% isopropanol solution until the residual epoxy test is negative, vacuum dry at 50°C to LOD≤5% to obtain alkylated hydroxypropyl methylcellulose;

[0055] The specific preparation process of the microcapsule NaHCO3 is as follows:

[0056] 1) Dry 100g of NaHCO3 under vacuum at 45°C for 2 hours, cool to 35°C and use as a bed material; heat 10g of glyceryl stearate to 90°C to melt, add 0.05g of lecithin and stir evenly, spray on the surface of the bed material, with air inlet temperature of 60°C, air outlet temperature of 35°C, spraying rate of 8g / min·kg bed material, atomized air of 1.2 bar, wall material weight gain of 10%, fluidize at room temperature for 5 minutes, and screen through a 40-mesh sieve to obtain microcapsule NaHCO3;

[0057] The preparation of the water-soluble tilmicosin premix specifically includes the following steps:

[0058] (1): Dissolve 3g polyvinylpyrrolidone K30, 0.6g citric acid and 0.2g tartaric acid in 1000mL of deionized water at 45℃, then add 10g tilmicosin phosphate, stir to disperse evenly, spray dry, with air inlet at 150℃, air outlet at 75℃, and atomized air at 2.4bar to obtain the master powder;

[0059] (2): Dissolve 20g of sulfobutyl-β-cyclodextrin in 100mL of deionized water at 40℃, add citric acid buffer to adjust the pH to 6.5, then add 8g of sodium gluconate and dissolve evenly to obtain a buffer softening synergistic solution.

[0060] (3): Dissolve tetrasodium glutamate diacetate in deionized water to obtain a 24wt% GLDA aqueous solution; dissolve alkylated hydroxypropyl methylcellulose in deionized water at 80℃ and cool to room temperature to obtain a 6wt% cellulose solution; spray the buffer softening synergistic liquid from step (2) onto 100g of binuclear seeds, with an air inlet temperature of 75℃, an outlet temperature of 44℃, and an atomized air temperature of 1.8 bar; feed liquid at 10g / min·kg, spray liquid at 300g / kg bed material, and simultaneously feed the mother powder from step (1) at a feeding rate of 12g / min·kg, with a target deposition of 300g / kg bed material; spray GLDA aqueous solution sequentially under the same temperature and control, with a spray liquid at 20g / kg bed material; and cellulose aqueous solution, adjusting the liquid feed rate to 5g / min·kg bed material and the spray liquid at 150g / kg bed material;

[0061] (4): After completing the spraying treatment in step (3), continue the spraying treatment under the same temperature and control. First, spray 15wt% mannitol aqueous solution at a spraying volume of 35g / kg of bed material; then feed microcapsule NaHCO3 at a quantitative amount of 5g / kg of bed material; finally, spray 4wt% lecithin solution at a spraying volume of 30g / kg of bed material; screen through a 40-mesh sieve, add 0.5% fumed silica by weight of the finished product and dry mix evenly, then seal with nitrogen to obtain water-soluble tilmicosin premix.

[0062] Example 3: A water-soluble tilmicosin premix, comprising the following raw materials: tilmicosin phosphate, citric acid, tartaric acid, polyvinylpyrrolidone K30, sulfobutyl-β-cyclodextrin, citrate buffer pair, sodium gluconate, tetrasodium diacetate of glutamate, alkylated hydroxypropyl methylcellulose, binuclear seeds, mannitol, microcapsule NaHCO3, fumed silica, and lecithin.

[0063] The citric acid buffer pair is composed of citric acid and sodium citrate in a 1:1 mass ratio;

[0064] The dual-core seed is prepared by mixing mannitol and anhydrous glucose in a mass ratio of 8:2.

[0065] The specific preparation process of the alkylated hydroxypropyl methylcellulose is as follows:

[0066] 1. Add 120g of hydroxypropyl methylcellulose to 1000mL of 80wt% isopropanol solution and stir until homogeneous to obtain a 12wt% homogeneous slurry. Slowly add NaOH solution to adjust the pH to 12.5, stir at 40°C for 30min, raise the temperature to 55°C, add 9.6mL of lauryl glycidyl ether dropwise, stir continuously at 300rpm and keep warm for 4h, cool to 35°C, adjust the pH to 7.5 with glacial acetic acid, filter, wash with 70wt% isopropanol solution until the residual epoxy value test is negative, and vacuum dry at 55°C until LOD ≤ 5% to obtain alkylated hydroxypropyl methylcellulose.

[0067] The specific preparation process of the microcapsule NaHCO3 is as follows:

[0068] 1) Dry 100g of NaHCO3 under vacuum at 50℃ for 4h, cool to 40℃ and use as bed material; heat 15g of glyceryl stearate to 90℃ to melt, add 0.15g of lecithin and stir evenly, spray on the surface of bed material, with air inlet temperature of 70℃, air outlet temperature of 40℃, spraying rate of 15g / min·kg bed material, atomized air of 0.8 bar, wall material weight gain of 15%, fluidize at room temperature for 10min, and screen through a 40-mesh sieve to obtain microcapsule NaHCO3;

[0069] The preparation of the water-soluble tilmicosin premix specifically includes the following steps:

[0070] (1): Dissolve 5g polyvinylpyrrolidone K30, 0.8g citric acid and 0.5g tartaric acid in 1000mL of 50℃ deionized water, then add 12g tilmicosin phosphate, stir to disperse evenly, spray dry, with air inlet temperature of 140℃, air outlet temperature of 85℃, and atomized air at 2bar to obtain master powder.

[0071] (2): Dissolve 30g of sulfobutyl-β-cyclodextrin in 100mL of deionized water at 50℃, add citric acid buffer to adjust the pH to 6.3, then add 12g of sodium gluconate and dissolve evenly to obtain a buffer softening synergistic solution;

[0072] (3): Dissolve tetrasodium glutamate diacetate in deionized water to obtain a 20wt% GLDA aqueous solution; dissolve alkylated hydroxypropyl methylcellulose in deionized water at 90℃ and cool to room temperature to obtain an 8wt% cellulose solution; spray the buffer softening synergistic liquid from step (2) onto 100g of binuclear seeds, with an air inlet temperature of 60℃, an outlet temperature of 48℃, and an atomized air temperature of 1.6 bar; feed liquid at 20g / min·kg, spray liquid at 400g / kg of bed material, and simultaneously feed the mother powder from step (1) at a feeding rate of 16g / min·kg, with a target deposition of 300g / kg of bed material; spray GLDA aqueous solution sequentially under the same temperature and control, with a spray liquid at 20g / kg of bed material; and cellulose aqueous solution, adjusting the liquid feed rate to 10g / min·kg of bed material and spray liquid at 180g / kg of bed material;

[0073] (4): After completing the spraying treatment in step (3), continue the spraying treatment under the same temperature and control. First, spray 15wt% mannitol aqueous solution with a spray volume of 45g / kg bed material; then feed microcapsule NaHCO3 quantitatively with a feeding volume of 10g / kg bed material; finally, spray 6wt% lecithin solution with a spray volume of 50g / kg bed material; screen through a 40-mesh sieve, add 1% fumed silica by weight of the finished product and dry mix evenly, seal with nitrogen, and obtain water-soluble tilmicosin premix.

[0074] Comparative Example 1: The operating parameters of Comparative Example 1 and Example 1 are basically the same. The main difference is that in Comparative Example 1, sulfobutyl-β-cyclodextrin is replaced with hydroxypropyl-β-cyclodextrin by mass; the other operating parameters are the same.

[0075] Comparative Example 2: The operating parameters of Comparative Example 2 and Example 1 are basically the same. The main difference is that GLDA aqueous solution is not sprayed in Comparative Example 2; the other operating parameters are the same.

[0076] Comparative Example 3: The operating parameters of Comparative Example 3 and Example 1 are basically the same. The main difference is that in Comparative Example 3, the mass of alkylated hydroxypropyl methylcellulose is replaced with hydroxypropyl methylcellulose; the other operating parameters are the same.

[0077] Comparative Example 4: The operating parameters of Comparative Example 4 and Example 1 are basically the same. The main difference is that only mannitol mononuclear was used in Comparative Example 4 and anhydrous glucose was not added; the other operating parameters are the same.

[0078] Experimental testing:

[0079] Acute toxicity test: Forty ICR mice, aged 7-9 weeks (half male and half female), were selected and divided into 8 groups (corresponding to Examples 1-3, Comparative Examples 1-4, and the blank control group with pure water, respectively). The mice were acclimatized for 7 days, with a slight fasting period 4 hours prior to the experiment, but free access to water. Initial weights were recorded. Mice were administered the drug via gavage at doses of 50 mg / kg and 150 mg / kg. Observations were conducted continuously from 0-4 hours after administration, and data were recorded on days 1, 2, 4, 7, 10, and 14. Weight change = (weight at test time - initial weight) / initial weight × 100% and daily feed intake (g / animal·day), and daily water intake (mL / animal·day). Calculate the water / feed ratio (mL / g) = daily water intake / daily feed intake, and the feed conversion ratio (g / g) = feed intake per unit time / weight gain per unit time. The test results of weight change are shown in Tables 1 and 4 below; the results of water-feed ratio change are shown in Tables 2 and 5; and the results of feed conversion ratio change are shown in Tables 3 and 6.

[0080] Table 1. Results of body weight change test after 50 mg / kg dose of tilmicosin premix.

[0081]

[0082] Table 2. Results of the test on the change in drug-to-material ratio at a dose of 50 mg / kg for tilmicosin premix.

[0083]

[0084] Table 3. Results of the drug-to-material weight ratio change test for tilmicosin premix at a dose of 50 mg / kg / Weight gain ≤ 0 is recorded as NA

[0085]

[0086] Table 4. Results of body weight change test after tilmicosin premixed solution at a dose of 150 mg / kg

[0087]

[0088] Table 5. Results of the test on the change in drug-to-material ratio at a dose of 150 mg / kg for tilmicosin premix.

[0089]

[0090] Table 6. Results of the test on the change in drug-to-material weight ratio of tilmicosin premix at a dose of 150 mg / kg / Weight gain ≤ 0 is recorded as NA.

[0091]

[0092] Based on the results in Tables 1-6 above, the tilmicosin premix prepared in the embodiments of the present invention is safe and stable. Acute administration tests verified its excellent safety profile; no obvious side effects were observed during the experiment, and no mice died. In Comparative Example 1, hydroxypropyl-β-cyclodextrin lacks a sulfobutyl anionic side chain, resulting in insufficient charge shielding and weak ion pairing ability against positively charged macrolides. Host-guest inclusion primarily relies on hydrophobic cavities, leading to a higher proportion of free drug and higher effective surface activity after gastric ingestion. This results in increased susceptibility to endogenous Ca2+. 2+ / Mg 2+ When in contact with dietary mineral particles, adsorption and bridging deposition are more likely to occur, resulting in increased short-term irritation and bitterness. Specifically, in the early stages, a higher water / feed ratio and a worse feed conversion ratio are observed, and weight gain recovery is also slower. After the 7th day, as adaptation and sedimentation gradually clear the sediment, the difference narrows, but it is still weaker than Example 1. Comparative Example 2 removed the sustained-release chelating layer, retaining only the fast-phase softening effect of sodium gluconate. In the initial stages of water / gastric ingestion, it can still reduce hardness ion interference to some extent, but when bile salts and gastric emptying introduce Ca... 2+ / Mg 2+ Continuing into the small intestine, formulations lacking delayed-release complexing ability are more prone to delayed turbidity and micro-deposition, causing mild mucosal discomfort and absorption fluctuations. Specifically, this manifests as slightly inhibited water / food intake around day 2, a slightly delayed recovery in the weight curve, and a slightly higher feed conversion ratio in the mid-term compared to Example 1. In Comparative Example 3, the unmodified hydroxypropyl methylcellulose lacks hydrophobic side chains and cannot form a stable transiently wetting amphiphilic membrane at the interface between particles and reconstituted solutions. This makes it more prone to microagglomeration and local concentration peaks during reconstitution. After entering the stomach, the probability of local supersaturation and recrystallization increases, thereby increasing short-term irritation and oral / gastric discomfort. Specifically, this manifests as a more significant decrease in food intake in the early stages, a higher water / feed ratio, and a delayed recovery in weight. The mononuclear system in Comparative Example 4 was more prone to producing fine powder and trace amounts of insoluble micro-clusters during production and reconstitution. The clarification rate and steady-state uniformity of the reconstituted solution were slightly inferior. Local high-concentration drug plaques were more likely to appear during gavage. The mechanical / osmotic stimulation of the gastric mucosa was increased in the short term, which was specifically manifested as mild feed intake inhibition and delayed weight gain in the early stage. The feed conversion ratio was also slightly higher in the middle stage. As the gastrointestinal tract self-regulates and deposits are cleared, the difference between the middle and late stages narrows.

[0093] Dissolution test: 400ppm hard water medium: 0.441g CaCl2·2H2O and 0.246g MgSO4·7H2O dissolved in 1L of deionized water; 800ppm hard water medium: 0.882g CaCl2·2H2O and 0.493g MgSO4·7H2O dissolved in 1L of deionized water; simultaneously, 0.5g / L bentonite, 0.25g / L zeolite, and 0.5g / L dicalcium phosphate dihydrate were added to the 400ppm hard water for mineral interference testing; 1000mL (400ppm / 800ppm / 400ppm+minerals) hard water medium was added to the jacketed cup, the temperature was kept constant at 25°C, stirring was started at 300rpm, pre-stirred for 2min for degassing, and 1g of the tilmicosin premix sample powder prepared in Example 1 and Comparative Examples 1-4 was added. At each time point, a 5 mL sample was taken and immediately replenished with an equal volume of blank medium of the same temperature and hardness to maintain a constant total volume. Samples were taken and filtered at t = 0.5 min, 1 min, 2 min, 5 min, and 10 min, and the dissolution rate of tilmicosin was determined by HPLC. The dissolution percentage (%) = total dissolution rate / initial volume × 100%. An additional 20 mL of the unfiltered sample was taken at 2 min and 5 min, and the turbidity NTU was measured (with the same hardness blank as zero). The 400 ppm dissolution test results are as follows: Figure 1 As shown; the 800ppm dissolution test results are as follows. Figure 2 As shown; the results of the 400ppm mineral challenge dissolution test are as follows. Figure 3 As shown in Table 7, turbidity tests under different hard water media were conducted.

[0094] Table 7. Turbidity changes of tilmicosin premix under different hard water media

[0095]

[0096] Based on Table 7 and Figure 1-3 Analysis of the results showed that the tilmicosin premix prepared in Example 1 of this invention had a steeper initial slope at 30-60s, higher cumulative dissolution rates at 120s and 5-10min, and the lowest NTU at 2min and 5min throughout the process. In Comparative Example 1, the hydroxypropyl-β-cyclodextrin lacked a sulfobutyl anionic side chain, resulting in significantly weakened charge shielding and anti-adsorption capabilities, and the tilmicosin cation site was more readily reacted with Ca. 2+ / Mg 2+The negatively charged clay / zeolite surface forms ion bridges and coordinate adsorption, resulting in low dissolution pressure throughout the entire time period, with the difference significantly amplified after the hardness increases or minerals are added. The abundance and large particle size of colloidal flocs resulted in the highest NTU at 2 min and 5 min, with the smallest drop at 5 min. In Comparative Example 2, after removing GLDA, fast-phase softening could still be maintained by sodium gluconate in the 30-60 s period, but from 120 s onwards, with the entry of new hardness ions and the participation of bile salts / phosphates, the lack of chelation coverage in the later time window led to a significant drop in the curve; correspondingly, the decrease in NTU at 5 min was not ideal, indicating that the Ca2+ in the later time window... 2+ / Mg 2+ The process is still driving trace redeposition or drug-mineral flocculation. In Comparative Example 3, after replacing amphiphilic modified cellulose with unmodified HPMC, the wetting and disaggregation upon entering water was slower, and the surface contact angle was higher, resulting in a lower initial dissolution time of 30-60s. At the same time, due to the lack of hydrophobic anchoring and surface stabilization, local supersaturation was more likely to induce microcrystal nucleation, forming a fine but persistent colloidal phase, resulting in a higher NTU at 2 min and a slower decrease at 5 min compared to Example 1. Although the chemical system was still present, it could be gradually improved through diffusion and dilution in the later stages, but it still showed slightly worse dissolution and clarification throughout the process under 800 ppm and mineral challenge media. Comparative Example 4 had a complete chemical formulation, but after changing to a single core, the uniformity of film thickness and the repeatability of the in-bed circulation trajectory of fluidized spraying decreased, and the probability of uneven fine powder and coating increased, resulting in a slight downward shift of the entire curve: the mass transfer resistance was greater in the early stage, and it was slightly slower within 120s; in the middle and later stages, it gradually caught up due to the continued presence of chemical protection, but the NTU of 2-5 min was always slightly higher than that of Example 1.

[0097] Stability Test: Tilmicosin premixes prepared in Example 1 and Comparative Examples 1-4 (samples were opened and then resealed, i.e., exposed for 5 minutes after opening, desiccant removed, and sealed with adhesive tape to simulate daily use) were placed at 40℃ / 75% humidity for 6 months. Samples were taken at 0, 1, 2, 3, and 6 months to test water content and turbidity (samples were placed in a 400ppm hard water medium, and turbidity NTU was measured at 2 minutes and 5 minutes). Changes in water content are shown below. Figure 4 As shown, the turbidity changes (2 min and 5 min) are as follows: Figure 5 and Figure 6 As shown, pH changes are as follows Figure 7 As shown.

[0098] based on Figure 4-7The results showed that the tilmicosin premix prepared in this embodiment exhibited the slowest increase in water content, the smallest pH drift, and the lowest NTU increase after 2-5 minutes of immersion in water, demonstrating excellent stability. In Comparative Example 1, the hydroxypropyl-β-cyclodextrin was a nonionic cyclodextrin, lacking the negatively charged soft shielding of the sulfonyl group. This resulted in greater hydrophilicity / hygroscopicity in the solid phase, softening of the membrane layer after absorbing water, and easier particle bridging and growth. However, the lack of shielding after immersion in water allowed tilmicosin to more readily combine with Ca... 2+ / Mg 2+ Ion bridging / adsorption occurs, NTU increases significantly and decreases slowly after 5 minutes. Under humid heat, the effective acidity of the buffer pair is easily fixed in the crystalline phase or consumed by trace metals, resulting in a decrease in equivalent acid capacity and the most significant pH surge. In Comparative Example 2, the solid phase lacks GLDA to occupy trace metals (Ca / Mg / Fe), making it more prone to metal bridging and micro-agglomeration after humid heat and moisture absorption, making redispersion difficult. In the water introduction phase, only sodium gluconate provides immediate softening, and after 120 seconds, there is a lack of sustained coordination, resulting in delayed turbidity. This is manifested by a faster increase and slower decrease in NTU within 2-5 minutes. The mild phase separation of the buffer during humid heat / hygroscopic absorption, combined with the participation of metal ions, results in a significant pH drift, but not as pronounced as in Comparative Example 1. Comparative Example 3 lost its hydrophobic side chain anchoring and interfacial stable phase, resulting in reduced membrane moisture resistance, more pronounced capillary hygroscopic absorption, and easier powder adhesion. After immersion in water, wetting / disaggregation was slow, and the probability of microcrystal nucleation was high, leading to a higher NTU at 2 minutes and a slower decline at 5 minutes. Membrane instability also made the effective buffer distribution and microenvironment more prone to drift, with the pH shift second only to Comparative Example 1. Comparative Example 4 had the same chemical formulation as Example 1, but the mononuclear formation worsened the film thickness uniformity and in-bed circulation trajectory. The higher proportion of fine powder and more weak points in the coating resulted in easier water vapor penetration and a higher moisture absorption curve. The redispersion consistency of the particle population was slightly worse after immersion in water, and the NTU was slightly higher throughout. However, the buffer system was not fundamentally destroyed, resulting in less pH drift.

[0099] Particle size distribution: The particle size distribution curve of the tilmicosin premix prepared in Example 1 was obtained using laser diffraction particle size analysis. The results are as follows: Figure 8 As shown.

[0100] based on Figure 8 Analysis shows that the percentage distribution of columnar particles exhibits a unimodal, slightly right-skewed log-normal distribution, and the red smooth curve represents the fitting of columnar frequency. The main peak is located at 240-260 μm, corresponding to a median particle size D. 50 Approximately 250 μm; the tails on both sides converge well, D 10 Approximately 120μm, D 90 Approximately 480 μm, span coefficient (D) 90 -D 10 ) / D 50Approximately 1.44; this indicates that during the spray granulation process of this invention, the droplet size, drying rate, and nucleation growth in the fluidized bed are stably locked within the same window, without the appearance of double peaks or shoulder peaks. The same-track circulation effect brought about by the isodense dual-nucleus strategy is also reflected as a single-peak distribution rather than a double-peak superposition. The proportion of fine powder on the left is extremely low, with low risk of surface dust exposure and segregation, which is beneficial for feeding and sieving; the proportion of coarse particles larger than 600μm at the tail end on the right is extremely low, indicating that excessive adhesion and secondary agglomeration are controlled, and no over-wetting or film bridging instability occurs in the spray section. In terms of performance correlation, D 50 Approximately 250μm, D 90 The ≤500μm range aligns with the present invention's established goal of rapid wetting and dissolution without excessive foaming: the particle size is small enough to provide specific surface area and uniform coating, and the narrow distribution ensures consistent microscopic mass transfer pathways during the resolution process, thus achieving higher and more stable dissolution and lower turbidity in hard water and mineral-interfering media.

[0101] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A water-soluble tilmicosin premix, characterized in that, The composition comprises the following raw materials: tilmicosin phosphate, citric acid, tartaric acid, polyvinyl pyrrolidone K30, sulfobutyl-beta-cyclodextrin, citric acid buffer pair, sodium gluconate, glutamic acid diacetic acid tetrasodium, alkylated hydroxypropyl methyl cellulose, double core seeds, mannitol, microcapsule NaHCO3, fumed silica and lecithin; The double core seeds are prepared by mixing mannitol and anhydrous glucose at a mass ratio of 8:2; The specific preparation process of the microcapsule NaHCO3 is as follows: 1): NaHCO3 is vacuum dried and cooled as bed material; glyceryl stearate is heated and melted, lecithin is added and stirred uniformly, sprayed on the surface of the bed material, fluidized at room temperature, screened, and the microcapsule NaHCO3 is obtained; The preparation of the water-soluble tilmicosin premix specifically includes the following steps: (1): polyvinyl pyrrolidone K30, citric acid and tartaric acid are dissolved in deionized water, then tilmicosin phosphate is added, stirred and dispersed uniformly, and spray dried to obtain a mother powder; (2): sulfobutyl-beta-cyclodextrin is dissolved in deionized water, the pH is adjusted by adding a citric acid buffer pair, then sodium gluconate is added and dissolved uniformly to obtain a buffer softening synergistic solution; (3): GLDA aqueous solution is obtained by dissolving glutamic acid diacetic acid tetrasodium in deionized water; cellulose solution is obtained by dissolving alkylated hydroxypropyl methyl cellulose in deionized water and cooling to room temperature; the buffer softening synergistic solution of step (2) is sprayed onto the double core seeds, and the mother powder of step (1) is fed synchronously; then GLDA aqueous solution and cellulose aqueous solution are sprayed in turn under the same temperature and control; (4): after the spraying process of step (3) is completed, continue the spraying process under the same temperature and control, first spray mannitol aqueous solution, then feed microcapsule NaHCO3 quantitatively, and finally spray lecithin solution; screen, add fumed silica and mix uniformly, seal with nitrogen, and obtain water-soluble tilmicosin premix.

2. The water-soluble tilmicosin premix according to claim 1, characterized in that, The citric acid buffer pair is composed of citric acid and sodium citrate at a mass ratio of 1:

1.

3. The water-soluble tilmicosin premix according to claim 1, characterized in that, The specific preparation process of the alkylated hydroxypropyl methyl cellulose is as follows: 1: hydroxypropyl methyl cellulose is added to an isopropyl alcohol solution, stirred uniformly to obtain a uniform slurry; NaOH solution is slowly added to adjust the pH, stirred, heated, and lauryl glycidyl ether is added dropwise, continuously stirred and kept warm, cooled, the pH is adjusted with glacial acetic acid, filtered, washed with isopropyl alcohol until the residual epoxy value test is negative, vacuum dried to obtain alkylated hydroxypropyl methyl cellulose; The ratio of the amount of lauryl glycidyl ether to hydroxypropyl methyl cellulose is 0.6-0.8 mL:10 g.

4. The water-soluble tilmicosin premix of claim 1, wherein, In step (1), the ratio of the amount of polyvinyl pyrrolidone, tilmicosin phosphate, citric acid, tartaric acid and deionized water is 0.3-0.5 g:1-1.2 g:0.06-0.08 g:0.02-0.05 g:100 mL.

5. The water-soluble tilmicosin premix of claim 1, wherein, In step (1), the spray drying parameters are: inlet air temperature 140-150℃, outlet air temperature 75-85℃, and atomizing air pressure 2-2.5 bar.

6. A water-soluble tilmicosin premix according to claim 1, characterized in that, In step (2), the ratio of sulfobutyl-β-cyclodextrin, sodium gluconate and deionized water is 2-3 g:0.8-1.2 g:10 mL.

7. The water-soluble tilmicosin premix of claim 1, wherein, In step (3), the spraying parameters of the buffer softening synergistic liquid are: air inlet 60-75 ℃, air outlet 44-48 ℃, atomizing air 1.6-2 bar; liquid feed 10-20 g / min·kg, liquid spray amount 300-400 g / kg bed material; when the cellulose aqueous solution is sprayed, the liquid feed speed is adjusted to 5-10 g / min·kg bed material.

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