Water-soluble tilmicosin premix and preparation method thereof

Abstract

The invention belongs to the technical field of veterinary preparations, and particularly relates to a water-soluble tilmicosin premix and a preparation method thereof. The tilmicosin phosphate sustained-release tablets are prepared from the following raw materials: tilmicosin phosphate, citric acid, tartaric acid, polyvinylpyrrolidone K30, sulfobutyl-beta-cyclodextrin, a citric acid buffer pair, sodium gluconate, tetrasodium glutamate diacetate, alkylated hydroxypropyl methyl cellulose, binuclear seeds, mannitol, microcapsules NaHCO3, fumed silica and lecithin. According to the preparation method, firstly, citric acid, tartaric acid and PVP are used for carrying out co-amorphization and spray drying on tilmicosin phosphate to prepare mother powder, so that the solubility is improved, and the recrystallization tendency is reduced; spraying a synergistic liquid inner layer containing sulfobutyl-beta-cyclodextrin and the like, and sequentially spraying a GLDA chelation layer, a modified cellulose hydrophilic film, a binuclear carrier, mannitol addition isolation, microcapsule NaHCO3, outer layer lecithin and fumed silica to optimize dissolution and stability.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of veterinary drug preparation, and particularly relates to a water-soluble tilmicosin premix and a preparation method thereof. BACKGROUND

[0002] Tilmicosin, as a 16-membered macrolide antibiotic, is widely used in the prevention and treatment of respiratory infections in ruminants, pigs and poultry. The common dosage forms at present include injection, premix for feed mixing and soluble powder for drinking water, etc. Injection administration has the problems of low individual operation compliance and high group administration cost; the efficacy of premix for feed mixing depends on the animal feed intake, and sick animals are prone to insufficient administration when they are off feed; while drinking water administration has the advantages of rapid onset and good group coverage, but it puts forward higher requirements for the solubility behavior, dissolution kinetics, clarity, hard water adaptability, administration pipeline compatibility and stability of the preparation in aqueous phase.

[0003] The current technical development of tilmicosin preparation for drinking water still faces many common challenges. First of all, there is a contradiction between solubility and clarity. Although tilmicosin is often used in the form of salt, its dissolution rate and final clarity are still significantly affected by pH value and ionic strength. Some existing formulations use strong acidification or a large amount of surfactants to promote dissolution, but this easily leads to a decrease in palatability, an increase in foam, turbidity of the solution, and even causes wall hanging of the drinking water line and clogging of the spray head; in high-hardness water or in the presence of mineral components such as bentonite, zeolite and calcium phosphate, the drug molecules are prone to electrostatic adsorption, ion bridging or co-precipitation, resulting in a decrease in free drug concentration and an increase in apparent turbidity. Secondly, the dissolution stability of traditional tilmicosin preparations is poor. As a macrolide compound, tilmicosin may undergo hydrolysis or recrystallization under high temperature and humidity conditions. Some soluble powders show delayed dissolution and decreased clarity after long-term storage or after experiencing cold and hot cycles, affecting the reliability of administration and the expected efficacy. In addition, traditional fine powders or simple physical mixing type powders are prone to moisture absorption and caking, have poor flowability, and are prone to separation after transportation and vibration, thereby leading to uneven concentration of secondary preparation, non-compliance of batch content uniformity, and operation safety risks caused by dust exposure. SUMMARY

[0004] The present application provides a water-soluble tilmicosin premix and a preparation method thereof to overcome the deficiencies of the prior art. To solve the problems of the existing water-soluble tilmicosin, such as easy adsorption and deposition in hard water / minerals, slow onset, turbidity, and poor transport segregation stability, the present application first co-amorphizes the drug with citric acid, tartaric acid, and PVP to improve the initial dissolution rate and heat and humidity stability. The inner layer is sprayed with sulfobutyl-beta-cyclodextrin, citric acid buffer pair, and sodium gluconate to effectively reduce the adsorption of the drug with minerals such as bentonite, zeolite, and calcium phosphate, and stabilize the pH of the system. The thin layer is sprayed with glutamic acid diacetate tetrasodium to provide short-term sustained chelation and inhibit the generation of turbidity in the later stage. The outer layer uses amphiphilic cellulose and lecithin to promote instantaneous wetting and inhibit drug recrystallization. The dual-core carrier is constructed by mannitol and anhydrous glucose, and the segmented spraying process is used to realize a uniform and segregation-resistant stable structure of the film layer.

[0005] The technical effects of the present application are realized by the following technical scheme: a water-soluble tilmicosin premix, which comprises the following raw materials: tilmicosin phosphate, citric acid, tartaric acid, polyvinylpyrrolidone K30, sulfobutyl-beta-cyclodextrin, citric acid buffer pair, sodium gluconate, glutamic acid diacetate tetrasodium, alkylated hydroxypropyl methyl cellulose, dual-core seeds, mannitol, microcapsule NaHCO3, fumed silica, and lecithin.

[0006] Further, the particle size distribution D 90 of the tilmicosin phosphate is 10-20 μm, i.e., the cumulative volume fraction in the particle size distribution reaches 90% at a particle size of 10-20 μm; Further, the citric acid buffer pair is composed of citric acid and sodium citrate at a mass ratio of 1:1. Further, the dual-core seeds are mixed and prepared by mannitol and anhydrous glucose at a mass ratio of 8:2. Further preferably, the particle size distribution D 50 of the mannitol is 150-250 μm, i.e., the cumulative volume fraction in the particle size distribution reaches 50% at a particle size of 150-250 μm. Further preferably, the particle size distribution D 50 of the anhydrous glucose is 90-140 μm. Further, the specific preparation process of the alkylated hydroxypropyl methyl cellulose is as follows: 1: Hydroxypropyl methylcellulose is added to an 80wt% isopropyl alcohol solution, stirred uniformly to obtain an 8-12wt% uniform slurry; slowly add NaOH solution, adjust pH to 11.5-12.5, stir at 30-40°C for 30min, increase temperature to 45-55°C, drop lauryl glycidyl ether, continue stirring at 300rpm and incubate for 2-4h, cool to 35°C, adjust pH to 7-7.5 with glacial acetic acid, suction filtration, 70wt% isopropyl alcohol solution wash until residual epoxy value test is negative, 50-55°C vacuum drying to LOD≤5%, to obtain alkylated hydroxypropyl methylcellulose; Further, the ratio of the use amount of lauryl glycidyl ether and hydroxypropyl methylcellulose is 0.6-0.8mL:10g; Further, the specific preparation process of the microcapsule NaHCO3 is as follows: 1): NaHCO3 is vacuum dried at 45-50°C for 2-4h, cooled to 35-40°C as bed material; glyceryl stearate is heated to 90°C to melt, 0.5-1% lecithin is added and stirred uniformly, sprayed on the surface of the bed material, inlet air 60-70°C, outlet air 35-40°C, spraying rate 8-15g / min·kg bed material, atomizing air 0.8-1.2bar, wall material weight gain 10-15%, fluidized at room temperature for 5-10min, screened with a 40mesh sieve, to obtain microcapsule NaHCO3; Another aspect of the present application is to provide a preparation method of a water-soluble tilmicosin premix, specifically comprising the following steps: (1): polyvinylpyrrolidone K30, citric acid and tartaric acid are dissolved in 45-50°C deionized water, then tilmicosin phosphate is added, stirred and dispersed uniformly, spray dried to obtain a mother powder; (2): sulfobutyl-β-cyclodextrin is dissolved in 40-50°C deionized water, citric acid buffer is added to adjust pH to 6.3-6.5, then sodium gluconate is added and dissolved uniformly to obtain a buffer softening synergistic solution; (3): tetrasodium glutamate diacetate is dissolved in deionized water to obtain a 20-25wt% GLDA aqueous solution; alkylated hydroxypropyl methylcellulose is dissolved in 80-90°C deionized water, cooled to room temperature to obtain a 6-8wt% cellulose solution; the buffer softening synergistic solution of step (2) is sprayed onto the double core seeds, and the mother powder of step (1) is simultaneously fed at a feeding speed of 12-16g / min·kg, with a target deposition of 300g / kg bed material; then GLDA aqueous solution is sprayed in sequence under the same temperature and control, with a spraying amount of 20g / kg bed material; cellulose aqueous solution is sprayed, with a spraying amount of 150-180g / kg bed material; (4): after the spraying treatment of step (3), continue the spraying treatment under the same temperature and control, first spray 15wt% mannitol aqueous solution, spray liquid amount 35-45g / kg bed material; then quantitatively feed microcapsule NaHCO3, feeding amount 5-10g / kg bed material; finally spray 4-6wt% lecithin solution, spray liquid amount 30-50g / kg bed material; screen through 40 mesh sieve, add 0.5-1% fumed silica of product quality, dry mix uniformly, store under nitrogen, obtain water-soluble tilmicosin premix; Further, in step (1), the ratio of the use amount 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; Further, in step (1), the spray drying parameters are: inlet air 140-150℃, outlet air 75-85℃, atomizing air 2-2.5bar; Further, in step (2), the ratio of the use amount of sulfobutyl-β-cyclodextrin, sodium gluconate and deionized water is 2-3g:0.8-1.2g:10mL; Further, in step (3), the spray parameters of the buffer softening synergistic solution are: inlet air 60-75℃, outlet air 44-48℃, atomizing air 1.6-2bar; liquid feed 10-20g / min·kg, spray liquid amount 300-400g / kg bed material; Further, in step (3), when spraying the cellulose aqueous solution, the liquid feed speed is adjusted to 5-10g / min·kg bed material.

[0007] The beneficial effects of the present application are as follows: Compared with the prior art, the present application firstly adopts citric acid and tartaric acid and polyvinylpyrrolidone to co-amorphize tilmicosin phosphate, and combines with the spray drying process, so that the drug is converted into a glassy state, a higher energy level but a limited structure, the apparent solubility of the drug is improved, and the recrystallization tendency of the drug under humid heat conditions is reduced, providing stable starting materials for subsequent water phase diffusion and solution clarification. The obtained mother powder surface is rich in polar groups and PVP segments, which accelerates the hydration rate, and does not introduce insoluble phases or strong complexing sites, which is beneficial to subsequent water phase solubilization and buffer system synergistic effect. Then the synergistic solution containing sulfobutyl-β-cyclodextrin, sodium citrate buffer pair and sodium gluconate is sprayed as the inner layer. In this system, cyclodextrin forms a host-guest inclusion structure with tilmicosin, effectively reducing the hydrophobic interaction and the exposure area of the charged sites of the drug in the water phase, thereby inhibiting the electrostatic adsorption and ion bridging of the drug on the surface of bentonite, zeolite and calcium-containing inorganic salts. The buffer system stabilizes the pH of the microenvironment on the surface of the particles in the weakly acidic range, which is more conducive to the dissolution of the salt type drug; sodium gluconate can form a complex with Ca2+ / Mg 2+ Mild complexation occurs, reducing the interference of water hardness ions on drug dissociation and diffusion, helping to obtain a clear or low turbidity solution.

[0008] To cover the impact of hardness ions entering the water system and gastrointestinal environment over time, the independent thin spray glutamic acid diacetic acid tetrasodium (GLDA) forms a slow-release chelating layer, maintaining effective Ca 2+ / Mg 2+ Capture capacity, reducing late-stage precipitation and secondary turbidity phenomena. Again, with a low dose of amphiphilic modified cellulose (alkylated hydroxypropyl methylcellulose) forming a hydrophilic film layer on the outside, significantly reducing the water contact angle, improving wetting and disaggregation speed, and inhibiting drug secondary crystallization and re-adsorption on the particle surface, shortening the time required to reach stable clarity from a kinetic point of view, while maintaining compatibility with the inner functional components without adverse reactions. In addition, the dual-core carrier of mannitol and anhydrous glucose is selected, and the particle size distribution is adjusted to make the traversal probability of the two types of seeds in the spray area and the uniformity of the coating more easily controlled, reducing the infiltration segregation in the transportation and secondary packaging process from the source. To avoid acid-base interaction during the storage period, a thin layer of mannitol is added between the functional inner layer and sodium bicarbonate as a barrier; the microcapsule sodium bicarbonate layer can quickly release a small amount of CO2 after entering the water, accelerating the pore wetting and disaggregation without changing the system pH and clarity. The outermost layer of low-content lecithin further reduces surface tension and improves compatibility with water system materials, reducing the risk of wall hanging and nozzle clogging; the terminal dry-mixed fumed silica improves powder flowability and reduces the tendency to bridge and cake. BRIEF DESCRIPTION OF DRAWINGS

[0009] Figure 1 The dissolution test results chart of the tilmicosin premix prepared in Example 1 and Comparative Examples 1-4 in 400 ppm hard water medium; Figure 2 The dissolution test results chart of the tilmicosin premix prepared in Example 1 and Comparative Examples 1-4 in 800 ppm hard water medium; Figure 3 The dissolution test results chart of the tilmicosin premix prepared in Example 1 and Comparative Examples 1-4 in 400 ppm mineral hard water medium; Figure 4 The water content change chart in the stability test of the tilmicosin premix prepared in Example 1 and Comparative Examples 1-4; Figure 5 The 2 min turbidity change chart in the stability test of the tilmicosin premix prepared in Example 1 and Comparative Examples 1-4; Figure 6 The 5 min turbidity change chart in the stability test of the tilmicosin premix prepared in Example 1 and Comparative Examples 1-4; Figure 7 pH change graph in the stability test of the tilmicosin premix prepared for Example 1 and Comparative Examples 1 to 4; Figure 8 Particle size distribution graph of the tilmicosin premix prepared for Example 1. DETAILED DESCRIPTION

[0010] The technical solutions of the present application will be described clearly and completely below in combination with the embodiments of the present application. Obviously, the described embodiments are only some of the embodiments of the present application, not all the embodiments. Unless otherwise specified, the raw materials involved in the present application are purchased through the conventional commercial channel. The experimental methods without specific conditions are the conventional methods and conventional conditions well-known in the art, or according to the conditions recommended by the instrument manufacturer.

[0011] Example 1: A water-soluble tilmicosin premix, which consists of the following raw materials: tilmicosin phosphate, citric acid, tartaric acid, polyvinylpyrrolidone K30, sulfobutyl-β-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.

[0012] The citric acid buffer pair is composed of citric acid and sodium citrate in a mass ratio of 1:1; The double-core seeds are prepared by mixing mannitol and anhydrous glucose in a mass ratio of 8:2; The specific preparation process of the alkylated hydroxypropyl methyl cellulose is as follows: 1: 100 g of hydroxypropyl methyl cellulose is added to 1000 mL of 80 wt% isopropyl alcohol solution, stirred uniformly to obtain a 10 wt% uniform slurry; NaOH solution is slowly added to adjust the pH to 12, stirred at 35°C for 30 min, warmed to 50°C, and 7 mL of lauryl glycidyl ether is added dropwise, continuously stirred at 300 rpm and incubated for 3 h, cooled to 35°C, and the pH is adjusted to 7.2 with glacial acetic acid, filtered, washed with 70 wt% isopropyl alcohol solution until the residual epoxy value test is negative, and vacuum dried at 52°C to LOD≤5%, to obtain alkylated hydroxypropyl methyl cellulose; The specific preparation process of the microcapsule NaHCO3 is as follows: 1): 100 g of NaHCO3 is vacuum dried at 48°C for 3 h, cooled to 38°C as bed material; 12 g of glyceryl stearate is heated to 90°C to melt, 0.096 g of lecithin is added and stirred uniformly, sprayed on the surface of the bed material, the inlet air temperature is 65°C, the outlet air temperature is 38°C, the spraying rate is 10 g / min·kg bed material, the atomizing air is 1 bar, the wall material weight gain is 12%, the fluidization is carried out at room temperature for 8 min, and the microcapsule NaHCO3 is obtained by screening with a 40 mesh sieve; The preparation of the water-soluble tilmicosin premix specifically comprises the following steps: (1): 4g polyvinylpyrrolidone K30, 0.7g citric acid and 0.3g tartaric acid are dissolved in 1000mL 48℃ deionized water, then 11g tilmicosin phosphate is added, stirred and dispersed uniformly, spray dried, inlet air 145℃, outlet air 80℃, atomizing air 2.5bar, to obtain a mother powder; (2): 25g sulfobutyl-β-cyclodextrin is dissolved in 100mL 45℃ deionized water, citric acid buffer pair is added to adjust the pH to 6.4, then 10g sodium gluconate is added and dissolved uniformly to obtain a buffer softening synergistic solution; (3): tetrasodium glutamate diacetate is dissolved in deionized water to obtain a 25wt% GLDA aqueous solution; alkylated hydroxypropyl methyl cellulose is dissolved in 85℃ deionized water, cooled to room temperature to obtain a 7wt% cellulose solution; the buffer softening synergistic solution of step (2) is sprayed onto 100g double core seeds, inlet air 70℃, outlet air 46℃, atomizing air 2bar; liquid feed 15g / min·kg, spray liquid amount 350g / kg bed material, simultaneously feeding the mother powder of step (1) at a feeding speed of 15g / min·kg, target deposition 300g / kg bed material; under the same temperature and control, GLDA aqueous solution is sprayed in turn, spray liquid amount 20g / kg bed material; cellulose aqueous solution, adjust the liquid feed speed to 8g / min·kg bed material, spray liquid amount 160g / kg bed material; (4): after completing the spraying process of step (3), continue the spraying process under the same temperature and control, first spray 15wt% mannitol aqueous solution, spray liquid amount 40g / kg bed material; then quantitatively feed microcapsule NaHCO3, feeding amount 8g / kg bed material; finally spray 5wt% lecithin solution, spray liquid amount 40g / kg bed material; screen through a 40 mesh sieve, add 0.8% fumed silica to the product quality, mix uniformly, nitrogen seal, to obtain a water-soluble tilmicosin premix.

[0013] Example 2: A water-soluble tilmicosin premix, the composition of which comprises the following raw materials: tilmicosin phosphate, citric acid, tartaric acid, polyvinylpyrrolidone K30, sulfobutyl-β-cyclodextrin, citric acid buffer pair, sodium gluconate, tetrasodium glutamate diacetate, alkylated hydroxypropyl methyl cellulose, double core seeds, mannitol, microcapsule NaHCO3, fumed silica and lecithin.

[0014] The citric acid buffer pair is composed of citric acid and sodium citrate in a mass ratio of 1:1; The double core seeds are prepared by mixing mannitol and anhydrous glucose in a mass ratio of 8:2; The specific preparation process of the alkylated hydroxypropyl methyl cellulose is as follows: 1: 80 g of hydroxypropyl methylcellulose was added to 1000 mL of 80 wt% isopropyl alcohol solution, stirred uniformly to obtain 8 wt% uniform slurry; slowly add NaOH solution, adjust pH to 11.5, stir at 30°C for 30 min, increase temperature to 45°C, add 4.8 mL of lauryl glycidyl ether, continue stirring at 300 rpm and incubate for 2 h, cool to 35°C, adjust pH to 7 with glacial acetic acid, filter, wash with 70 wt% isopropyl alcohol solution until the residual epoxy is negative, vacuum drying at 50°C to LOD≤5%, to obtain alkylated hydroxypropyl methylcellulose; The specific preparation process of the microcapsule NaHCO3 is as follows: 1): 100 g of NaHCO3 was vacuum dried at 45°C for 2 h, cooled to 35°C as bed material; 10 g of glyceryl stearate was heated to 90°C to melt, 0.05 g of lecithin was added and stirred uniformly, sprayed on the surface of the bed material, the inlet air temperature was 60°C, the outlet air temperature was 35°C, the spraying rate was 8 g / min·kg bed material, the atomizing air pressure was 1.2 bar, the wall material weight gain was 10%, the fluidization time was 5 min at room temperature, and the microcapsule NaHCO3 was obtained by screening with a 40 mesh sieve; The preparation of the water-soluble tilmicosin premix specifically includes the following steps: (1): 3 g of polyvinylpyrrolidone K30, 0.6 g of citric acid and 0.2 g of tartaric acid were dissolved in 1000 mL of 45°C deionized water, then 10 g of tilmicosin phosphate was added, stirred and dispersed uniformly, and spray dried, with an inlet air temperature of 150°C, an outlet air temperature of 75°C, and an atomizing air pressure of 2.4 bar, to obtain a mother powder; (2): 20 g of sulfobutyl-β-cyclodextrin was dissolved in 100 mL of 40°C deionized water, the pH was adjusted to 6.5 with citric acid buffer, then 8 g of sodium gluconate was added and dissolved uniformly to obtain a buffer softening synergistic solution; (3): Tetrasodium glutamate diacetate was dissolved in deionized water to obtain a 24 wt% GLDA aqueous solution; alkylated hydroxypropyl methylcellulose was dissolved in 80°C deionized water, and cooled to room temperature to obtain a 6 wt% cellulose solution; the buffer softening synergistic solution of step (2) was sprayed onto 100 g of double-nucleus seeds, with an inlet air temperature of 75°C, an outlet air temperature of 44°C, and an atomizing air pressure of 1.8 bar; the liquid feed was 10 g / min·kg, the liquid spray amount was 300 g / kg bed material, and the mother powder of step (1) was fed synchronously at a feeding speed of 12 g / min·kg, with a target deposition of 300 g / kg bed material; under the same temperature and control, GLDA aqueous solution was sprayed in turn, with a liquid spray amount of 20 g / kg bed material; the cellulose aqueous solution was adjusted to a liquid feed speed of 5 g / min·kg bed material, and the liquid spray amount was 150 g / kg bed material; (4): after the spraying process of step (3) is completed, continue the spraying process under the same temperature and control, first spray 15wt% mannitol aqueous solution, spraying liquid amount 35g / kg bed material; then quantitatively feed microcapsule NaHCO3, feeding amount 5g / kg bed material; finally spray 4wt% lecithin solution, spraying liquid amount 30g / kg bed material; screen through 40 mesh sieve, add 0.5% fumed silica of product quality, dry mix uniformly, seal with nitrogen, and obtain water-soluble tilmicosin premix.

[0015] Example 3: A water-soluble tilmicosin premix, which consists of the following raw materials: tilmicosin phosphate, citric acid, tartaric acid, polyvinylpyrrolidone K30, sulfobutyl-β-cyclodextrin, citric acid buffer pair, sodium gluconate, glutamic acid diacetic acid tetrasodium, alkylated hydroxypropyl methyl cellulose, double-core seed, mannitol, microcapsule NaHCO3, fumed silica and lecithin.

[0016] The citric acid buffer pair is composed of citric acid and sodium citrate in a mass ratio of 1:1; The double-core seed is mixed and prepared by mannitol and anhydrous glucose in a mass ratio of 8:2; The specific preparation process of the alkylated hydroxypropyl methyl cellulose is as follows: 1: add 120g hydroxypropyl methyl cellulose into 1000mL 80wt% isopropyl alcohol solution, stir uniformly to obtain 12wt% uniform slurry; slowly add NaOH solution, adjust pH to 12.5, stir at 40°C for 30min, increase temperature to 55°C, drop 9.6mL lauryl glycidyl ether, continue stirring at 300rpm and keep for 4h, decrease temperature to 35°C, adjust pH to 7.5 with glacial acetic acid, filter, wash with 70wt% isopropyl alcohol solution until the residual epoxy value test is negative, vacuum dry at 55°C to LOD≤5%, and obtain alkylated hydroxypropyl methyl cellulose; The specific preparation process of the microcapsule NaHCO3 is as follows: 1): dry 100g NaHCO3 at 50°C for 4h, cool to 40°C as bed material; melt 15g glyceryl stearate at 90°C, add 0.15g lecithin, stir uniformly, spray on the surface of the bed material, inlet air temperature 70°C, outlet air temperature 40°C, spraying rate 15g / min·kg bed material, atomizing air 0.8bar, wall material weight gain 15%, fluidize at room temperature for 10min, screen through 40 mesh sieve, and obtain microcapsule NaHCO3; The preparation of the water-soluble tilmicosin premix specifically includes the following steps: (1): 5 g of polyvinylpyrrolidone K30, 0.8 g of citric acid and 0.5 g of tartaric acid were dissolved in 1000 mL of deionized water at 50°C, then 12 g of tilmicosin phosphate was added, stirred and uniformly dispersed, and spray dried at an inlet temperature of 140°C and an outlet temperature of 85°C with an atomizing air pressure of 2 bar to obtain a mother powder; (2): 30 g of sulfobutyl-β-cyclodextrin was dissolved in 100 mL of deionized water at 50°C, citric acid buffer was added to adjust the pH to 6.3, then 12 g of sodium gluconate was dissolved to obtain a buffer softening synergistic solution; (3): Tetrasodium glutamate diacetate was dissolved in deionized water to obtain a 20wt% GLDA aqueous solution; alkylated hydroxypropyl methyl cellulose was dissolved in deionized water at 90°C, and cooled to room temperature to obtain an 8wt% cellulose solution; the buffer softening synergistic solution of step (2) was sprayed onto 100 g of double-core seeds at an inlet temperature of 60°C and an outlet temperature of 48°C with an atomizing air pressure of 1.6 bar; the liquid feed rate was 20 g / min·kg, the liquid spray amount was 400 g / kg of bed material, and step (1) mother powder was simultaneously fed at a feeding speed of 16 g / min·kg, and the target deposition was 300 g / kg of bed material; under the same temperature and control conditions, GLDA aqueous solution was sprayed in sequence, the liquid spray amount was 20 g / kg of bed material; the liquid feed rate of the cellulose aqueous solution was adjusted to 10 g / min·kg of bed material, and the liquid spray amount was 180 g / kg of bed material; (4): After the spraying process of step (3) was completed, the same temperature and control conditions were continued, 15wt% mannitol aqueous solution was first sprayed, the liquid spray amount was 45 g / kg of bed material; then a certain amount of microcapsule NaHCO3 was fed, the feeding amount was 10 g / kg of bed material; finally, 6wt% lecithin solution was sprayed, the liquid spray amount was 50 g / kg of bed material; screened through a 40 mesh sieve, 1% fumed silica was added to the product quality and mixed evenly, and nitrogen was sealed to obtain a water-soluble tilmicosin premix.

[0017] Comparative Example 1: The operating process parameters of Comparative Example 1 and Example 1 were basically kept consistent, the main difference being that sulfobutyl-β-cyclodextrin was replaced by hydroxypropyl-β-cyclodextrin in Comparative Example 1; the remaining operating parameters were kept consistent.

[0018] Comparative Example 2: The operating process parameters of Comparative Example 2 and Example 1 were basically kept consistent, the main difference being that no GLDA aqueous solution was sprayed in Comparative Example 2; the remaining operating parameters were kept consistent.

[0019] Comparative Example 3: The operating process parameters of Comparative Example 3 and Example 1 were basically kept consistent, the main difference being that alkylated hydroxypropyl methyl cellulose was replaced by hydroxypropyl methyl cellulose in Comparative Example 3; the remaining operating parameters were kept consistent.

[0020] Comparative Example 4: The operation flow parameters of Comparative Example 4 and Example 1 were basically kept consistent, the main difference was that only mannitol mononuclei was used in Comparative Example 4, no anhydrous glucose was added; the rest of the operation parameters were kept consistent.

[0021] Test test: Acute toxicity test: ICR mice 7-9 weeks old, half male and half female, a total of 40, divided into 8 groups (corresponding to Examples 1-3 and Comparative Examples 1-4 and a blank control group of pure water), adaptive feeding for 7 days, 4 hours before the test, light fasting without water, weighing the initial weight; according to the dosage of 50mg / kg and 150mg / kg, gavage administration, 0-4h after administration, continuous observation, and record the body weight change=(test time weight-initial weight) / initial weight x 100% and daily feed intake (g / only·day), and daily water intake (mL / only·day), and water / feed ratio (mL / g)=daily water intake / daily feed intake, and feed weight ratio (g / g)=intake of feed weight per unit time / body weight increase per unit time; the body weight change test results are shown in Tables 1 and 4; the water / feed ratio change results are shown in Tables 2 and 5; the feed weight ratio change is shown in Tables 3 and 6.

[0022] Table 1. Test results of body weight change of tilmicosin premix at a dose of 50mg / kg

[0023] Table 2. Test results of water / feed ratio change of tilmicosin premix at a dose of 50mg / kg

[0024] Table 3. Test results of feed weight ratio change of tilmicosin premix at a dose of 50mg / kg / weight gain≤0, record NA

[0025] Table 4. Test results of body weight change of tilmicosin premix at a dose of 150mg / kg

[0026] Table 5. Test results of water / feed ratio change of tilmicosin premix at a dose of 150mg / kg

[0027] Table 6. Test results of feed weight ratio change of tilmicosin premix at a dose of 150mg / kg / weight gain≤0, record NA

[0028] Based on the result analysis of the above Tables 1-6, the prepared timicosin premix of the embodiment of the application is safe and stable, and the safety performance is excellent verified by acute administration test, no obvious side effects occur in the experiment process, and no death of the test mice occurs. The hydroxypropyl-beta-cyclodextrin in Comparative Example 1 lacks sulfobutyl anion side chain, and the charge shielding and weak ion pairing ability for the positively charged macrolide are insufficient, the host-guest inclusion mainly relies on the hydrophobic cavity, resulting in higher free drug ratio and effective surface activity after entering the stomach, and when encountering endogenous Ca 2+ / Mg 2+ When combined with dietary mineral particles, adsorption and bridging deposition are more likely to occur, short-term stimulation and bitter taste increase, which is specifically manifested in that higher water / food ratio and poorer food weight ratio are observed in the early stage, and the body weight recovery is also slower; after the 7th day, the difference is reduced with the gradual removal of adaptation and deposition, but it is still weaker than that of Example 1. Comparative Example 2 removes the slow-release chelating layer and only retains the sodium gluconate fast-phase softening, which can still reduce the interference of hardness ions to a certain extent in the initial stage of water entering / stomach, but when the bile salts and Ca 2+ / Mg 2+ When continuing to enter the small intestine section, the prescription lacking the slow-release complexing ability is more likely to cause late-onset turbidity and micro-deposition, causing slight discomfort and absorption fluctuation of the mucosa, which is specifically manifested in that the water consumption / food intake is slightly inhibited around the 2nd day, the body weight curve recovery is slightly delayed, and the food weight ratio is slightly higher than that of Example 1 in the middle period. The unmodified hydroxypropyl methylcellulose in Comparative Example 3 lacks a hydrophobic side chain, and cannot form a stable instant hydrophilic membrane on the surface interface of the particles and the reconstituted solution, so that micro-aggregation and local concentration peaks are more likely to occur during the reconstitution process; the local supersaturation and recrystallization probability increase after entering the stomach, thereby increasing the short-term stimulation and discomfort in the oral cavity / stomach, which is specifically manifested in that the food intake decreases more obviously in the early stage, the water / food ratio is high, and the body weight recovery is delayed. The single-core system of Comparative Example 4 is more likely to produce fine powder and trace insoluble micro-aggregates during production and reconstitution, the reconstituted solution is slightly inferior in clarity speed and steady state uniformity, and local high-concentration drug liquid patches are more likely to occur during gavage, thereby increasing the mechanical / permeation stimulation of the stomach mucosa in the short term, which is specifically manifested in that the food intake is slightly inhibited and the body weight recovery is delayed in the early stage, the food weight ratio is slightly high in the middle period, and the difference is reduced in the middle and late periods with the self-regulation of the gastrointestinal tract and the removal of the deposition.

[0029] Dissolution test: 400 ppm concentration hard water medium: dissolve 0.441 g CaCl2·2H2O and 0.246 g MgSO4·7H2O in 1 L deionized water; 800 ppm concentration hard water medium: dissolve 0.882 g CaCl2·2H2O and 0.493 g MgSO4·7H2O in 1 L deionized water; at the same time, add 0.5 g / L bentonite, 0.25 g / L zeolite and 0.5 g / L calcium hydrogen phosphate dihydrate to the 400 ppm hard water to conduct mineral interference test; add 1000 mL (400 ppm / 800 ppm / 400 ppm+minerals) hard water medium to the jacketed cup, constant temperature to 25°C, start stirring at 300 rpm, pre-stir for 2 min to degas, add 1 g of tilmicosin premix sample powder prepared by Example 1 and Comparative Examples 1-4, take 5 mL at each time point, immediately make up with the same volume of blank medium of the same temperature and hardness, maintain the total volume constant, take samples for filtration at t=0.5 min, 1 min, 2 min, 5 min and 10 min respectively, determine the tilmicosin dissolution amount by HPLC, dissolution percentage (%) = total dissolution amount of sampling / initial amount x 100%; additionally take 20 mL of pre-filtered sample solution at 2 min and 5 min respectively, measure turbidity NTU (with the same hardness blank as zero point); the results of 400 ppm dissolution test are shown in Figure 1 ; the results of 800 ppm dissolution test are shown in Figure 2 ; the results of 400 ppm mineral challenge dissolution test are shown in Figure 3 ; the turbidity test under different hard water media is shown in Table 7.

[0030] Table 7. Turbidity change of tilmicosin premix under different hard water media

[0031] Based on the results analysis of Table 7 and Figures 1-3 , the tilmicosin premix prepared by Example 1 of the present application has a steeper initial slope of 30-60 s, higher cumulative dissolution of 120 s and 5-10 min, and the lowest NTU throughout 2 min and 5 min. In Comparative Example 1, the hydroxypropyl-β-cyclodextrin has no sulfobutyl anion side chain, and the charge shielding and anti-adsorption ability are significantly weakened, so the tilmicosin cationic site is more prone to be adsorbed by Ca 2+ / Mg 2+, the negatively charged clay / zeolite surface forms ion bridges and coordination adsorption, resulting in a low dissolution pressure throughout the period, and the gap is significantly enlarged with increasing hardness or the addition of minerals; the colloidal flocs are large in number and size, showing the highest NTU at 2 min and 5 min, and the smallest backfall at 5 min. In Comparative Example 2, GLDA is removed, and the fast phase softening in the 30-60 s period can still be maintained by sodium gluconate, but from 120 s, with the participation of new hardness ions and cholate / phosphate, the later period lacks chelation coverage, and the curve is obviously out of line; correspondingly, the NTU at 5 min is not ideal, indicating that the Ca 2+ / Mg 2+ is still driving trace redeposition or drug-mineral flocculation. In Comparative Example 3, unmodified HPMC is used to replace the amphiphilic modified cellulose, and the wetting and deagglomeration in water are slow, and the surface interfacial contact angle is high, resulting in a low initial dissolution in the 30-60 s period; at the same time, due to the lack of hydrophobic anchoring and surface stabilization, local supersaturation is more likely to induce microcrystal nucleation, forming small but persistent colloidal phases, which makes the NTU at 2 min high, and the decrease at 5 min slower than in Example 1; although the chemical system is still present, it can gradually catch up with diffusion and dilution in the later period, but it still shows slightly poor dissolution and clarification throughout the period under the challenge of 800 ppm and minerals. In Comparative Example 4, the chemical prescription is complete, but after being changed to a single core, the film thickness uniformity of fluidized spraying and the repeatability of the bed circulation track decrease, and the probability of fine powder and uneven coating of the finished product increases, resulting in a slight downward shift of the whole curve: the mass transfer resistance is greater in the early stage, and it is slightly slower within 120 s; the chemical protection is still present in the middle and late stages, and it gradually catches up, but the NTU at 2-5 min is always slightly higher than that in Example 1.

[0032] Stability test: The temixixacin premix prepared in Example 1 and Comparative Examples 1-4 (after opening, resealing, i.e. opening the bag and exposing for 5 min, removing the desiccant, sealing with a rubber strip, simulating daily use) was placed in 40°C / 75% humidity for 6 months, and the water content and turbidity (taking samples in 400 ppm concentration hard water medium, and taking samples to measure turbidity NTU at 2 min and 5 min, respectively) were tested at 0 months, 1 month, 2 months, 3 months and 6 months, respectively. The change in water content is shown in Figure 4 , the change in turbidity (2 min and 5 min) is shown in Figure 5 and Figure 6 , and the change in pH is shown in Figure 7 .

[0033] Based on Figures 4-7The prepared tilmicosin premix of the embodiment has the slowest increase in water content, the smallest pH drift, the lowest increase in NTU in 2-5 minutes after entering water, and excellent stability. The hydroxypropyl-β-cyclodextrin in Comparative Example 1 is a non-ionic cyclodextrin, which lacks sulfobutyl negative electric shielding, is more hydrophilic / hygroscopic in the solid phase, and the film layer softens after containing water, and the particles are more likely to bridge and grow; after entering water, the shielding is lacking, and tilmicosin is more likely to combine with Ca 2+ / Mg 2+ form ion bridges / adsorption, NTU increases significantly and falls slowly in 5 minutes, the effective acidity of the buffer pair is easily fixed in the crystal phase or consumed by trace metals under hygrothermal conditions, the equivalent acid capacity decreases, and the pH upsurge is the most obvious. The solid phase stage in Comparative Example 2 lacks GLDA occupation of trace metals (Ca / Mg / Fe), and is more likely to form metal bridging-micro-agglomeration after hygroscopicity under hygrothermal conditions, and is difficult to disperse again; only sodium gluconate softens immediately during the water entering stage, and lacks sustained coordination after 120 seconds, resulting in delayed turbidity, which is manifested by faster NTU increase and slower decrease in 2-5 minutes, and the buffer is slightly phase-separated under hygrothermal / hygroscopic conditions, and metal ions participate, the pH drift is obvious but not as much as Comparative Example 1. Comparative Example 3 loses the hydrophobic side chain anchoring and the stable phase of the surface interface, the film layer has reduced resistance to moisture, capillary hygroscopicity is more obvious, and the powder is more likely to be wet and sticky, wetting / dispersion is slow after entering water, the probability of microcrystal nucleation is high, NTU is high in 2 minutes, and falls slowly in 5 minutes; the instability of the film layer also makes the effective buffer distribution and the microenvironment more likely to drift, and the pH upsurge is only second to Comparative Example 1. Comparative Example 4 has the same formula chemistry as Example 1, but the single core makes the uniformity of the film thickness and the in-bed circulation trajectory deteriorate, the proportion of fine powder is high, there are more weak points in the coating, water vapor is more likely to penetrate, and the hygroscopicity curve rises; the consistency of the particle group is slightly poor after entering water, and the NTU is slightly high throughout; the buffer system has not been fundamentally destroyed, so the pH drift is small.

[0034] Particle size distribution: the particle size distribution curve of the tilmicosin premix prepared in Example 1 was obtained by laser diffraction particle size analysis method, and the results are shown in Figure 8 .

[0035] Based on Figure 8 analysis, the columnar percentage distribution shows a single peak, slightly right-biased, lognormal distribution characteristics, and the red smooth curve is a fitting of the columnar frequency; the main peak is located at 240-260 μm, corresponding to the median particle size D 50 about 250 μm; the tails on both sides converge well, D 10 about 120 μm, and D 90 about 480 μm, the span coefficient (D 90 -D 10 ) / D 50about 1.44; this indicates that in the spray granulation process of the present application, the droplet size in the fluidized bed, the drying rate and the nucleation and growth are stably locked in the same window, and there is no double-peak or shoulder peak, and the same-track circulation effect brought by the equal-density double-nucleus strategy is also reflected as a single-peak distribution instead of double-peak superposition. The proportion of fine powder on the left side is extremely low, the surface dust exposure and segregation risk is low, which is conducive to feeding and sieving; the proportion of coarse particles greater than 600 μm on the right side is extremely low, which indicates that excessive bonding and secondary agglomeration are controlled, and there is no over-wetting or membrane bridging instability phenomenon in the spraying section. In terms of performance correlation, D 50 about 250 μm, D 90 ≤500 μm interval is consistent with the established target of the present application: fast wetting, fast dissolution and no excessive foaming; the particle size is small enough to provide specific surface area and uniform film coating, and the distribution is narrow so that the micro-mass transfer path in the reconstitution process is consistent, so that higher and more stable dissolution and lower turbidity can be obtained in hard water and mineral interference medium.

[0036] Although embodiments of the present application have been shown and described, it is to be understood that various modifications, substitutions, replacements and variations can be made to these embodiments without departing from the principles and spirit of the present application, and the scope of the present application 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.

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

1.

3. A water-soluble tilmicosin premix according to claim 2, characterized in that, The double core seeds are prepared by mixing mannitol and anhydrous glucose in a mass ratio of 8:

2.

4. The water-soluble tilmicosin premix according to claim 3, characterized in that, The specific preparation process of the alkylated hydroxypropyl methyl cellulose is as follows: Hydroxypropyl methyl cellulose is added into an isopropyl alcohol solution, stirred uniformly to obtain a uniform slurry; NaOH solution is slowly added to adjust pH, stirred, heated, and lauryl glycidyl ether is added dropwise, continuously stirred and incubated, cooled, and pH is adjusted with glacial acetic acid, suction filtered, washed with isopropyl alcohol solution 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.

5. A water-soluble tilmicosin premix according to claim 4, characterised in that, 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 microcapsule NaHCO3 is obtained.

6. A process for the preparation of a water-soluble tilmicosin premix according to any one of claims 1 to 5, characterized in that, 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 tetrasodium glutamate diacetate 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.

7. A process for the preparation of a water-soluble tilmicosin premix according to claim 6, characterized in that, 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.

8. A process for the preparation of water-soluble tilmicosin premix according to claim 6, characterized in that, In step (1), the spray drying parameters are: inlet air 140-150℃, outlet air 75-85℃, and atomizing air 2-2.5 bar.

9. A process for the preparation of a water-soluble tilmicosin premix according to claim 8, characterized in that, In step (2), the ratio of the amount of sulfobutyl-beta-cyclodextrin, sodium gluconate, mother powder and deionized water is 2-3 g:0.8-1.2 g:10 mL.

10. A process for the preparation of a water-soluble tilmicosin premix according to claim 9, characterized in that, In step (3), the buffer softening dispersion spray parameters are: inlet air 60-75°C, outlet air 44-48°C, atomizing air 1.6-2 bar; liquid feed 10-20 g / min·kg, spray liquid 300-400 g / kg bed material; the cellulose aqueous solution is sprayed by adjusting the liquid feed speed to 5-10 g / min·kg bed material.

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