CN117860706A - Tilmicosin enteric-coated preparation and preparation method thereof - Google Patents

Abstract

The invention provides an enteric-coated preparation of tilmicosin and a preparation method thereof, and relates to the technical field of veterinary medicines. The tilmicosin enteric-coated preparation provided by the invention is prepared by organically combining chitosan and tilmicosin, preparing tilmicosin microcapsules with targeted aggregation function by taking xanthan gum as a capsule wall material, preparing pellets by extruding the microcapsules and proper auxiliary materials, and enteric-coating the prepared pellets. The tilmicosin enteric-coated preparation technical product provided by the invention is 'overgastric', the stomach is not released, the irritation of the drug to gastric mucosa is avoided, the enteric-coated preparation is dissolved and absorbed in intestinal tracts, and the absorption and utilization rate of the drug is improved. Compared with the common tilmicosin preparation, the tilmicosin enteric-coated preparation can realize anti-inflammatory and inflammation recovery promotion effects at low dosage, and has important social benefit, economic benefit and environmental benefit.

Description

Tilmicosin enteric-coated preparation and preparation method thereof

Technical Field

The invention relates to the technical field of veterinary medicines, in particular to an enteric-coated preparation of tilmicosin and a preparation method thereof.

Background

By the end of 2025, the large-scale farm above 50% carries out the action of reducing the resistance of cultivation, establishes a perfect and strict veterinary drug safe use management system, standardizes scientific drug administration, and comprehensively realizes the prescription drug system, the veterinary drug holiday system and the 'veterinary drug standard use' promise system.

At present, the incidence of infectious diseases of livestock and poultry is continuously rising, which causes great economic loss of the breeding industry. Tilmicosin is a semisynthetic macrolide antibiotic used in livestock and poultry, and similar to other macrolides, has the characteristics of rapid absorption, low antibacterial concentration, long half-life and the like, and has high concentration in lung and milk. Tilmicosin is used for treating pneumonia caused by Pasteurella multocida, actinobacillus pleuropneumoniae and Pasteurella multocida, has a good treatment effect on mycoplasma, streptococcus and staphylococcus aureus infected by pigs, cattle and sheep, and is also used for preventing and treating mastitis of ruminants and poultry respiratory infection caused by easy-induced substances. Because tilmicosin has strong antibacterial action, and can improve animal organism immunity, the tilmicosin has no cross resistance with other antibiotics commonly used in clinic, and has become the first choice medicine for antibacterial in recent years. The tilmicosin dosage form recorded in part of the chinese beast pharmacopoeia of 2015 edition comprises: injection, solution and premix. The time for cutting off the delivery is 1700 or more in the existing product approval documents, and the clinical use amount is huge. However, because tilmicosin injection has high toxicity, the clinical application is very few; solutions are affected by cost and convenience of administration, and the clinical dosage is limited; the tilmicosin premix has very large clinical dosage, and has limited clinical application due to problems of palatability and medication cost.

Therefore, the tilmicosin preparation with better palatability is researched and developed, and the tilmicosin preparation has important economic and social benefits. In order to solve the defects of the traditional dosage form, the invention researches the tilmicosin enteric preparation of a secondary coating process, the technology is 'overgastric' and the stomach is not released, the irritation of the medicine to gastric mucosa is avoided, the 'enteric' and the enteric dissolution and absorption are realized, and the absorption and utilization rate of the medicine is improved.

Disclosure of Invention

(one) solving the technical problems

Aiming at the defects of the prior art, the invention provides an enteric-coated preparation of tilmicosin and a preparation method thereof.

(II) technical scheme

In order to achieve the above purpose, the invention is realized by the following technical scheme:

on the one hand, the invention provides an enteric preparation of tilmicosin, which comprises the following raw materials in parts by weight: 10-40 parts of tilmicosin, 5-20 parts of chitosan, 5-30 parts of xanthan gum, 5-30 parts of dextrin, 5-30 parts of corn starch, 0-10 parts of acrylic resin II and 0-10 parts of polyvinyl alcohol titanate (PVAP).

Further, the enteric preparation comprises the following raw materials in parts by weight: 20-30 parts of tilmicosin, 5-15 parts of chitosan, 10-25 parts of xanthan gum, 10-25 parts of dextrin, 10-25 parts of corn starch, 3-8 parts of acrylic resin II and 3-8 parts of polyvinyl alcohol titanate (PVAP).

Further, the enteric preparation comprises the following raw materials in parts by weight: 25 parts of tilmicosin, 15 parts of chitosan, 20 parts of xanthan gum, 20 parts of dextrin, 10 parts of corn starch, 5 parts of acrylic resin II and 3 parts of polyvinyl alcohol titanate (PVAP).

On the other hand, the invention also provides a preparation method of the tilmicosin enteric preparation, which is prepared according to the following steps:

(1) Adding the chitosan with the weight portions into purified water with the amount of 8-10 times, and swelling for 4-6 hours for standby to obtain a mixed solution 1;

(2) Adding 4-6 times of purified water into the tilmicosin in parts by weight, and then slowly adding 50-60% wt of phosphoric acid solution until the pH value of the solution is 3.5-4.0 to obtain a mixed solution 2;

(3) Adding the mixed solution 2 into the mixed solution 1 under the stirring condition, and preserving the temperature at 40 ℃ for 30 minutes to obtain mixed solution 3;

(4) Taking the xanthan gum in parts by weight, adding 5-10 times of purified water, and swelling for 4-6 hours to obtain a mixed solution 4;

(5) Uniformly mixing the mixed solution 3 and the mixed solution 4, regulating parameters of centrifugal spray drying equipment, wherein the inlet temperature is 220-240 ℃, the outlet temperature is 85-95 ℃, the rotating speed of a centrifugal atomizer is 10000-15000rpm, and the feeding speed is 1500-2000mL/min, so as to prepare microcapsules with the particle size of 0.1-0.15 mm;

(6) Mixing the tilmicosin microcapsule obtained in the step (5) with the dextrin and the corn starch in parts by weight, extruding, granulating, rounding, drying, and preparing the pellet with the particle size of 0.3-0.45 mm.

(7) Taking the acrylic resin II and polyvinyl alcohol titanate in parts by weight, and adding 5-10 times of 95% ethanol for dissolution to obtain enteric coating liquid;

(8) Adding the pellets obtained in the step (6) and the enteric coating liquid obtained in the step (7) into a fluidized bed coating granulator, wherein the atomization pressure is 0.40-0.60bar, the inlet temperature is 45-50 ℃, the flow rate of the coating liquid is 500mL/min, the coating weight is increased by 5-6%, and the tilmicosin enteric preparation with the water content less than 5% is obtained.

Further, in the step (2), the mass fraction of phosphoric acid is 50% by weight.

(III) beneficial effects

The tilmicosin enteric-coated preparation provided by the invention is prepared by organically combining chitosan and tilmicosin to obtain embedded particles, performing primary pelleting on the particles to obtain pellets with a targeted aggregation function, and performing secondary pelleting to obtain the tilmicosin enteric-coated preparation with over-gastrointestinal dissolution and quick release in intestinal tracts.

The chitosan can effectively increase the phagocytic function and the hydrolase activity of the macrophage, and after the macrophage is activated, the phagocytic function of the macrophage can kill tumor cells and the like, can secrete various immune factors to regulate other cellular immunity and humoral immunity, and can also remarkably promote the capacity of spleen cells to generate antibodies. Targeted aggregation of tilmicosin makes it easy to aggregate in acidic macrophage lysosomes due to the two basic amino groups in its molecular structure. According to the invention, the chitosan and the tilmicosin are organically combined through the hydrogen bond action by utilizing the phosphoric acid, so that the chitosan and the tilmicosin are synergistic, the signal on-line reaction in macrophages is initiated, the phagocytic function and the immune function of the macrophages are further enhanced, and the antibacterial and anti-inflammatory effects of the tilmicosin are remarkably improved.

The tilmicosin enteric-coated preparation provided by the invention can realize the effects of insoluble in stomach and quick release in intestinal canal, avoid adverse reactions caused by the long-time action of tilmicosin on stomach, effectively improve the bioavailability of tilmicosin in animal bodies, and shows that the drug effective amount of 10 mg/kg/bw group of the preparation is equivalent to the drug effective amount of 20 mg/kg/bw group of the conventional product in terms of inflammatory factors and anti-inflammatory corpuscles through evaluation of the effect of an animal model of LPS-induced pneumonia, and has better clinical effect, reduced clinical dosage and better palatability. Compared with the common tilmicosin preparation, the tilmicosin enteric-coated preparation can realize anti-inflammatory and anti-inflammatory effects at low dosage, and has important social benefit, economic benefit and environmental benefit.

Drawings

Fig. 1 is a schematic structural diagram of an enteric-coated preparation of tilmicosin according to the present invention.

FIG. 2 shows the expression levels of TNF- α (A), IL-10 (B) and IL-1β (C) in lung tissue of mice in each group; p <0.05, < P <0.01, compared to LPS group.

Detailed Description

For the purpose of making the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the technical solutions in the embodiments of the present invention will be clearly and completely described in the following in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.

Example 1

An enteric-coated preparation of tilmicosin is prepared by organically combining chitosan and tilmicosin to prepare embedded particles, performing primary pelleting on the particles to obtain pellets with a targeting aggregation function, performing secondary pelleting to obtain an enteric-coated preparation of tilmicosin with over-gastrointestinal dissolution and quick release in intestinal tract, and the structural schematic diagram is shown in figure 1.

The enteric preparation comprises the following raw materials in parts by weight: 35 parts of tilmicosin, 18 parts of chitosan, 26 parts of xanthan gum, 22 parts of dextrin, 18 parts of corn starch, 8 parts of acrylic resin II and 6 parts of polyvinyl alcohol titanate (PVAP); the preparation method comprises the following steps:

(1) Adding the chitosan with the weight portions into purified water with the amount of 8-10 times, and swelling for 4-6 hours for standby to obtain a mixed solution 1;

(2) Adding 4-6 times of purified water into the tilmicosin in parts by weight, and then slowly adding 50% wt of phosphoric acid solution until the pH value of the solution is 3.5-4.0 to obtain a mixed solution 2;

(3) Adding the mixed solution 2 into the mixed solution 1 under the stirring condition, and preserving the temperature at 40 ℃ for 30 minutes to obtain mixed solution 3;

(4) Taking the xanthan gum in parts by weight, adding 5 times of purified water, and swelling for 6 hours to obtain a mixed solution 4;

(5) Uniformly mixing the mixed solution 3 and the mixed solution 4, regulating parameters of centrifugal spray drying equipment, wherein the inlet temperature is 220 ℃, the outlet temperature is 95 ℃, the rotation speed of a centrifugal atomizer is 10000rpm, the feeding speed is 2000mL/min, and preparing microcapsules with the particle size of 0.1-0.15 mm;

(6) Mixing the tilmicosin microcapsule obtained in the step (5) with the dextrin and the corn starch in parts by weight, extruding, granulating, rounding, drying, and preparing the pellet with the particle size of 0.3-0.45 mm.

(7) Taking the acrylic resin II and polyvinyl alcohol titanate in parts by weight, and adding 5-10 times of 95% ethanol for dissolution to obtain enteric coating liquid;

(8) Adding the pellets obtained in the step (6) and the enteric coating liquid obtained in the step (7) into a fluidized bed coating granulator, wherein the atomization pressure is 0.50bar, the inlet temperature is 50 ℃, the flow rate of the coating liquid is 500mL/min, the coating weight is increased by 5%, and the tilmicosin enteric preparation with the water content less than 5% is obtained.

Example 2

The difference between this example and example 1 is that the enteric preparation comprises the following raw materials in parts by weight: 10 parts of tilmicosin, 5 parts of chitosan, 5 parts of xanthan gum, 5 parts of dextrin, 5 parts of corn starch, 1 part of acrylic resin II and 0.5 part of polyvinyl alcohol titanate (PVAP)

Example 3

The difference between this example and example 1 is that the enteric preparation comprises the following raw materials in parts by weight: 40 parts of tilmicosin, 20 parts of chitosan, 30 parts of xanthan gum, 30 parts of dextrin, 30 parts of corn starch, 10 parts of acrylic resin II and 10 parts of polyvinyl alcohol titanate (PVAP)

Example 4

The difference between this example and example 1 is that the enteric preparation comprises the following raw materials in parts by weight: 20 parts of tilmicosin, 5 parts of chitosan, 10 parts of xanthan gum, 10 parts of dextrin, 10 parts of corn starch, 3 parts of acrylic resin II and 3 parts of polyvinyl alcohol titanate (PVAP).

Example 5

The difference between this example and example 1 is that the enteric preparation comprises the following raw materials in parts by weight: 30 parts of tilmicosin, 15 parts of chitosan, 25 parts of xanthan gum, 20 parts of dextrin, 12 parts of corn starch, 8 parts of acrylic resin II and 6 parts of polyvinyl alcohol titanate (PVAP).

Example 6

The difference between this example and example 1 is that the enteric preparation comprises the following raw materials in parts by weight: 22 parts of tilmicosin, 12 parts of chitosan, 18 parts of xanthan gum, 16 parts of dextrin, 20 parts of corn starch, 6 parts of acrylic resin II and 4 parts of polyvinyl alcohol titanate (PVAP).

Example 7

The difference between this example and example 1 is that the enteric preparation comprises the following raw materials in parts by weight: 25 parts of tilmicosin, 15 parts of chitosan, 20 parts of xanthan gum, 20 parts of dextrin, 10 parts of corn starch, 5 parts of acrylic resin II and 3 parts of polyvinyl alcohol titanate (PVAP).

Test examples

The beneficial effects of the tilmicosin enteric preparation in clinical application are further illustrated by the influence of anti-inflammatory factors and anti-inflammatory corpuscles in the LPS induced pneumonia animal model.

1 Experimental materials

1.1 laboratory animals

C57BL/6 mice, SPF grade, male, 5-6 weeks old, weight 18-20g,72 (purchased from Beijing Fukang Biotechnology Co., ltd., license number: SCXK (Beijing) 2019-0008, animal qualification number: SCXK (relaxation) 2021-0015, and animal house of SPF grade in Henan university of traditional Chinese medicine laboratory animal center, the laboratory unit uses license number: SYXK (relaxation) 2020-0004. Animal raising environment: temperature (20-25)) DEG C, relative humidity (55+ -5)%, 12h illumination, free drinking water ingestion. Animal experiment accords with Henan traditional Chinese medicine university laboratory animal ethical approval number: DWLL2022040156.

1.2 major Experimental reagents and materials

1.3 Main laboratory apparatus

2 Experimental methods

2.1 mouse model establishment and animal grouping for pneumonia

The supine head position of the mice after moderate anesthesia is fixed on a 45-degree inclined plane, the silk thread passes through the incisor to fix the neck part to enable the neck part to extend to the position, the trachea is exposed, a 1mL syringe which is rinsed by the medicine absorbs 70 mu L of LPS after absorbing 300 mu L of air in advance each time, the LPS is slowly injected after penetrating into the trachea by 0.5-1 cm through the cricoid membrane, the pre-absorbed air is quickly injected, the mice are vertically placed, and the mice are rotated for 3 weeks, so that the LPS is uniformly distributed in the lung, the wound is sutured, and the mice are naturally awake. 72 mice were randomly divided into 6 groups of 12 mice each, and the airways of the blank group were given the same volume of physiological saline; LPS group and administration group all airway administration 5mg/kg LPS solution; tilmicosin group (active pharmaceutical powder, effective dose is 20 mg/kg), high, medium and low groups (effective doses are 20mg/kg, 10mg/kg and 5mg/kg respectively) of the tilmicosin enteric preparation of the invention are respectively administered before molding, 1 time a day and 2 days continuously.

2.2 detection index

2.2.1ELISA the levels of the pro-inflammatory factors TNF- α, IL-1β, and anti-inflammatory factor IL-10 in lung tissue were measured.

Taking cells in a good logarithmic phase of growth state, inoculating RAW264.7 cells into 24 pore plates at the density of 5 multiplied by 105 cells per well and PBMCs at the density of 7 multiplied by 105 cells per well, respectively giving corresponding concentration and 2mL of medicine to each group, culturing for 1 to 8 hours, sucking cell culture solution of each group, centrifuging at 4 ℃ for 20min at 1000g, collecting supernatant solution, detecting the content of IL-1 beta, TNF-alpha and IL-10 in the supernatant of the culture solution by using an ELISA method, and performing the steps completely referring to the instructions of IL-1 beta, TNF-alpha and IL-10 detection kits.

2.2.2qRT-PCR method to detect the effect of mRNA expression levels of macrophage iNOS, COX-2. Cells in a good logarithmic phase of growth state are taken and inoculated into 6-hole plates at the density of 1X 106 cells per hole, each group is given 2mL of corresponding concentration and medicine, supernatant is sucked and removed after 18h of culture, PBS is used for 2 times, and total RNA of the cells is extracted by adopting a Trizol method. And (3) carrying out experiments according to the procedures of the amplification kit, and analyzing the relative expression quantity of the target gene by taking beta-actin as an internal reference. The sequences are shown in Table 1.

TABLE 1 primer sequences

2.2.3Western blot detection of iNOS protein expression

Taking cells in a log phase with good growth state, inoculating the cells in a 6-hole plate at the density of 1X 106 cells per hole, giving 2mL of each group of corresponding concentration and medicine, culturing for 18h, absorbing and discarding supernatant, adding lysate, centrifuging for 10min at 12000g, and absorbing the supernatant for quantitative detection of BCA protein. SDS-PAGE was performed according to 25. Mu.g/well of protein loading, and the ECL chromogenic kit developed to analyze the grey value of the bands with Image. Beta-actin was used as a reference for analytical calculation of iNOS protein expression levels.

2.3 data statistics and analysis

Data were statistically analyzed using GraphPad Prism 10.0 (GraphPad Software) software. All raw data are expressed using mean ± standard deviation (n ± SD). The comparison between groups uses one-way analysis of variance to compare the statistical differences between groups. P <0.05 significance difference; p <0.01 is a very significant difference.

3 results

3.1 Effect of the enteric-coated tilmicosin preparation of the present invention on the amounts of the pro-inflammatory factors TNF-alpha, IL-1 beta, and anti-inflammatory factor IL-10 in pulmonary tissue of a murine model of pneumonia

LPS treatment significantly increased TNF- α expression levels in lung tissue (P < 0.01) compared to lung tissue of mice in the blank group; in contrast, the levels of TNF- α expression tended to be significantly reduced in the case of treatment with the tilmicosin enteric preparation of the present invention at different doses, wherein the levels of TNF- α expression in lung tissue of the tilmicosin enteric preparation of the present invention at high dose (P < 0.01), medium dose (P < 0.01), and low dose (P < 0.01) were significantly statistically different from that of the LPS group, and no significant statistical difference was observed in comparison with the tilmicosin group, as shown in fig. 2A.

LPS treatment tended to decrease IL-10 expression levels in lung tissue compared to lung tissue of mice in the blank group; in the case of treatment with different doses of the tilmicosin enteric-coated preparation of the invention, the expression level of IL-10 tends to increase, and although the comparison has no obvious statistical difference, the tilmicosin enteric-coated preparation of the invention has the tendency of improving inflammation; and compared with tilmicosin groups, the IL-10 expression level of the medium and low dose groups has no obvious statistical difference, and the result is shown in figure 2B.

LPS treatment significantly increased the expression level of IL-1β in lung tissue compared to lung tissue of mice in the blank group (P < 0.01); in the case of treatment with different doses of the tilmicosin enteric preparation of the present invention, the expression level of IL-1β tends to be significantly reduced, wherein the expression level of IL-1β in lung tissue of the high dose (P < 0.05) and medium dose (P < 0.01) of the tilmicosin enteric preparation of the present invention is significantly statistically different from that of the LPS group; there was no significant statistical difference between the high dose group and the tilmicosin group, and the medium dose group and the tilmicosin group, and the results are shown in fig. 2C.

The LPS treatment can induce the reduction of anti-inflammatory factors IL-10 and the rise of pro-inflammatory factors TNF-alpha and IL-1 beta, the anti-inflammatory factor secretion amount after the tilmicosin enteric preparation is treated is maximum, the pro-inflammatory factor level is obviously lower than that of a tilmicosin group, and the effective amount of 10mg/kg.bw is the most right advantage in the aspect of inflammatory factor expression. 5mg/kg. Bw, still effective.

3.2 Effect of novel tilmicosin particles on macrophage iNOS and COX-2mRNA expression levels under LPS conditions

Compared with Control group, RAW264.7 cell has significantly reduced expression level of iNOS and COX-2mRNA after LPS intervention (P < 0.01); compared with LPS group, the expression level of iNOS and COX-2mRNA was significantly reduced in the high and medium dose administration groups (P < 0.01) (Table 2)

Table 2ASC1, NRLP3, caspase-1 and GAPDH Gray Scale ratio (mean+ -SD, n=3)

Note that: blank to LPS group ratio, Δp <0.05, ΔΔp <0.01; post-administration to LPS group ratio, P <0.05, P <0.01

3.3 Effect of the enteric-coated tilmicosin preparation of the present invention on the level of the macrophage secreted iNOS protein under LPS conditions

Compared to Control group, the macrophage iNOS protein level was significantly elevated (P < 0.01) in the LPS group (table 2). Compared with LPS group, the enteric-coated preparation of tilmicosin of the invention has significantly reduced level of iNOS protein expressed by macrophages at different dosages (P < 0.01); significant decrease in macrophage iNOS protein level in medium and low dose groups (P < 0.01) (table 2)

Conclusion 4

The results show that after the tilmicosin enteric-coated preparation disclosed by the invention is used for treating, the effective dose of the preparation is equivalent to that of a conventional product, namely, the effective dose of the preparation is 20 mg/kg/bw, and the content of inflammatory cells and the expression level of inflammatory mediators in lung tissues of mice with pneumonia can be obviously improved. Compared with the prior tilmicosin crude drug powder, the tilmicosin enteric-coated preparation can realize anti-inflammatory and anti-inflammatory effects at low dosage, and has important social benefit, economic benefit and environmental benefit.

The above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims (5)

1. The tilmicosin enteric-coated preparation is characterized by comprising the following raw materials in parts by weight: 10-40 parts of tilmicosin, 5-20 parts of chitosan, 5-30 parts of xanthan gum, 5-30 parts of dextrin, 5-30 parts of corn starch, 0-10 parts of acrylic resin II and 0-10 parts of polyvinyl alcohol titanate (PVAP).

2. The tilmicosin enteric-coated preparation according to claim 1, wherein the enteric-coated preparation comprises the following raw materials in parts by weight: 20-30 parts of tilmicosin, 5-15 parts of chitosan, 10-25 parts of xanthan gum, 10-25 parts of dextrin, 10-25 parts of corn starch, 3-8 parts of acrylic resin II and 3-8 parts of polyvinyl alcohol titanate (PVAP).

3. The tilmicosin enteric-coated preparation according to claim 1, wherein the enteric-coated preparation comprises the following raw materials in parts by weight: 25 parts of tilmicosin, 15 parts of chitosan, 20 parts of xanthan gum, 20 parts of dextrin, 10 parts of corn starch, 5 parts of acrylic resin II and 3 parts of polyvinyl alcohol titanate (PVAP).

4. A method for preparing an enteric formulation of tilmicosin according to any one of claims 1 to 3, wherein the enteric formulation is prepared by:

(1) Adding the chitosan with the weight portions into purified water with the amount of 8-10 times, and swelling for 4-6 hours for standby to obtain a mixed solution 1;

(2) Adding 4-6 times of purified water into the tilmicosin in parts by weight, and then slowly adding 50-60% wt of phosphoric acid solution until the pH value of the solution is 3.5-4.0 to obtain a mixed solution 2;

(3) Adding the mixed solution 2 into the mixed solution 1 under the stirring condition, and preserving the temperature at 40 ℃ for 30 minutes to obtain mixed solution 3;

(4) Taking the xanthan gum in parts by weight, adding 5-10 times of purified water, and swelling for 4-6 hours to obtain a mixed solution 4;

(5) Uniformly mixing the mixed solution 3 and the mixed solution 4, regulating parameters of centrifugal spray drying equipment, wherein the inlet temperature is 220-240 ℃, the outlet temperature is 85-95 ℃, the rotating speed of a centrifugal atomizer is 10000-15000rpm, and the feeding speed is 1500-2000mL/min, so as to prepare microcapsules with the particle size of 0.1-0.15 mm;

(6) Mixing the tilmicosin microcapsule obtained in the step (5) with the dextrin and the corn starch in parts by weight, extruding, granulating, rounding, drying, and preparing into pellets with the particle size of 0.3-0.45 mm;

(7) Taking the acrylic resin II and polyvinyl alcohol titanate in parts by weight, and adding 5-10 times of 95% ethanol for dissolution to obtain enteric coating liquid;

(8) Adding the pellets obtained in the step (6) and the enteric coating liquid obtained in the step (7) into a fluidized bed coating granulator, wherein the atomization pressure is 0.40-0.60bar, the inlet temperature is 45-50 ℃, the flow rate of the coating liquid is 500mL/min, the coating weight is increased by 5-6%, and the tilmicosin enteric preparation with the water content less than 5% is obtained.

5. The method for preparing an enteric-coated preparation of tilmicosin according to claim 4, wherein in the step (2), the mass fraction of phosphoric acid is 50% wt.