A prophylactic pharmaceutical preparation for porcine reproductive and respiratory syndrome and a method for preparing the same

Abstract

This invention discloses a preventive drug formulation for porcine reproductive and respiratory syndrome (PRRS) and its preparation method. The drug formulation uses tylosin tartrate as the active ingredient, loaded onto a blank cellulose carrier to obtain drug carrier nanoparticles, which are then coated with a blocking solution. The blocking solution is obtained by dispersing methacrylate-ethyl acrylate copolymer, triethyl citrate, and talc in deionized water. This invention utilizes the technical characteristics of synthesizing a spirocyclic phosphate diacyl chloride intermediate using pentaerythritol and phosphorus oxychloride, and reacting it with guanidine hydrochloride to construct a guanidine-functionalized crosslinking agent. This results in a guanidine-based intermediate with a rigid spirocyclic structure, providing stable crosslinking sites and spatial framework support for subsequent cellulose crosslinking, achieving the fundamental technical effect of constructing a three-dimensional network porous carrier framework.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically referring to a preventive pharmaceutical preparation for porcine reproductive and respiratory syndrome and its preparation method. Background Technology

[0002] Porcine reproductive and respiratory syndrome (PRRS), also known as blue ear disease, is a highly contagious, immunosuppressive infectious disease caused by porcine reproductive and respiratory syndrome virus (PRRSV). PRRSV is a single-stranded positive-sense RNA virus with two serotypes: European and American. The two serotypes share only about 60% nucleotide homology, and the viral genome is prone to mutation. In recent years, highly pathogenic strains, NADC30-like, and NADC34-like variants have emerged continuously, and antigenic drift is significant.

[0003] The core harm of this disease lies in its immunosuppressive properties and high pathogenicity. PRRSV specifically targets porcine alveolar macrophages, directly damaging the body's immune system and causing a significant decrease in the disease resistance of pig herds. This not only makes them susceptible to secondary infections such as classical swine fever, streptococcal disease, and Haemophilus parasuis infection, but also causes the failure of other vaccines. The disease is most severe in pregnant sows and piglets. Infected pregnant sows exhibit reproductive disorders such as abortion, stillbirth, weak piglets, and mummified fetuses, resulting in a significant decrease in the survival rate of piglets in the farrowing house. Infected piglets develop severe respiratory symptoms, with body temperature rising to 42°C, accompanied by respiratory distress, dehydration, and other symptoms, with a mortality rate that can reach up to 100%. Infected finishing pigs experience stunted growth, with feed intake decreasing by more than 7%, feed utilization decreasing by 15%, and the time to market delayed by about 25 days.

[0004] Currently, the prevention and control of PRRS relies primarily on vaccination, supplemented by symptomatic drug treatment and biosafety measures. However, all of these approaches have significant shortcomings in their effectiveness. Vaccines are mainly divided into two categories: inactivated vaccines and live attenuated vaccines. Inactivated vaccines are highly safe, with no risk of virulence reversion or shedding, and are convenient to store and transport. However, they have weak immunogenicity, extremely low ability to induce cellular immunity, require multiple high-dose immunizations, and have very poor cross-protection against variant strains. In some pig farms, the antibody positivity rate after immunization is less than 40%, failing to provide effective protection. Live attenuated vaccines have a rapid onset of action, quickly inducing an immune response and offering high protection against homologous strains. However, they pose significant safety risks, including a high risk of virulence reversion and the potential for recombination with wild-type strains to generate new variants. Furthermore, immunized pigs are prone to persistent infection, becoming latent sources of infection on pig farms. The protection rate of classic live attenuated strains against highly pathogenic PRRSV is only about 75%, which is insufficient to meet actual prevention and control needs.

[0005] In terms of drug control, macrolide drugs such as tilmicosin and tylosin are commonly used in clinical practice to inhibit PRRSV replication in macrophages. At the same time, antibiotics such as doxycycline and enrofloxacin are used to control secondary bacterial infections. However, long-term use of these drugs can easily lead to drug resistance in strains and there are drug residue problems, which do not comply with relevant food safety regulations. Traditional chemical antiviral drugs such as ribavirin are restricted in use in livestock and poultry farming, and there are currently no specific anti-PRRSV chemical drugs. They can only relieve clinical symptoms and cannot achieve preventive control of the disease. Traditional Chinese medicine (TCM) preparations have become an important direction for PRRS prevention and control research due to their advantages of multiple targets, low residues, and low likelihood of inducing drug resistance. Compound preparations such as Astragalus polysaccharide and Fuzheng Jiedu San have good immunomodulatory effects. Hypericin, Indigo naturalis, and Zanthoxylum bungeanum extract can significantly inhibit PRRSV replication in vitro. Compound preparations such as Qingwen Baidu San and Wuming Gaore San have certain therapeutic effects on PRRS. However, most existing TCM preparations are powders or decoctions, with single dosage forms, low bioavailability, and unstable preventive effects. They also lack standardized preparation processes and quality control systems, resulting in large differences in efficacy between batches. At the same time, most preparations focus on treatment after the onset of the disease, and there is insufficient research and development of special preparations for disease prevention, making it difficult to promote and apply them in large-scale pig farms. Summary of the Invention

[0006] To address the above issues and overcome the shortcomings of existing technologies, this invention provides a preventative drug formulation for porcine reproductive and respiratory syndrome (PRRS) and its preparation method. This invention utilizes the technical characteristics of synthesizing a spirocyclic phosphate diacyl chloride intermediate using pentaerythritol and phosphorus oxychloride, and then reacting it with guanidine hydrochloride to construct a guanidine-functionalized crosslinking agent. This results in a guanidine-based intermediate with a rigid spirocyclic structure, providing stable crosslinking sites and spatial framework support for subsequent cellulose crosslinking, thus achieving the fundamental technical effect of constructing a three-dimensional network porous carrier framework.

[0007] To achieve the above objectives, the technical solution adopted by the present invention is as follows: The present invention proposes a preventive drug preparation for porcine reproductive and respiratory syndrome. The drug preparation uses tartrate tylosin as the active substance, which is loaded onto a blank cellulose carrier to obtain drug carrier nanoparticles, and then coated with a blocking liquid. The blocking liquid is obtained by dispersing methacrylate-ethyl acrylate copolymer, triethyl citrate and talc in deionized water.

[0008] The raw materials for preparing the pharmaceutical formulation include the following components in parts by weight: 60-70 parts of drug carrier nanoparticles, 15-20 parts of methacrylate-ethyl acrylate copolymer, 3-5 parts of triethyl citrate, and 1-3 parts of talc.

[0009] Preferably, in the drug carrier nanoparticles, the mass ratio between tartrate tylosin and blank cellulose carrier is 1:1-2;

[0010] Preferably, the method for preparing the blank cellulose carrier specifically includes the following steps:

[0011] A1. Under a nitrogen atmosphere, phosphorus oxychloride was dissolved in anhydrous acetonitrile, and the reaction temperature was increased to carry out a reflux reaction. After the reaction was completed, pentaerythritol and triethylamine were added, and the temperature was maintained to carry out a second reflux reaction. After the reaction was completed, the mixture was distilled under reduced pressure, and hexane was added to the residue and stirred. The mixture was filtered to remove the triethylamine hydrochloride precipitate. The filtrate was concentrated to dryness under reduced pressure to obtain the spirocyclic phosphate diacyl chloride intermediate.

[0012] Preferably, in step A1, the molar ratio between phosphorus oxychloride and pentaerythritol is 4-6:1;

[0013] Preferably, in step A1, the molar ratio between triethylamine and pentaerythritol is 4.4-4.6:1;

[0014] Preferably, in step A1, the reaction temperature of the first reflux reaction is 80-90℃, the reaction time of the first reflux reaction is 30-60 min, the reaction temperature of the second reflux reaction is 80-90℃, and the reaction time of the second reflux reaction is 8-12 h;

[0015] A2. Under a nitrogen atmosphere, the spirocyclic phosphate diacyl chloride intermediate prepared in step A1 was dissolved in anhydrous DMF, guanidine hydrochloride was added, and after mixing evenly, triethylamine was added. Under light-protected conditions, the reaction temperature was increased to carry out the substitution reaction. After the reaction was completed, the mixture was cooled, and the reaction system was poured into ice water. After the precipitate was formed, it was filtered, the filter cake was collected, and dried to obtain the guanidine intermediate.

[0016] Preferably, in step A2, the molar ratio between the spirocyclic phosphate diacyl chloride intermediate and guanidine hydrochloride is 1:2.0-2.4;

[0017] Preferably, in step A2, the molar ratio between the spirocyclic phosphate diacyl chloride intermediate and triethylamine is 1:4.0-4.5;

[0018] Preferably, in step A2, the reaction temperature of the substitution reaction is 60-70°C, and the reaction time of the substitution reaction is 6-10 h;

[0019] A3. Disperse microcrystalline cellulose in anhydrous DMF, allow it to swell fully for 2-4 hours, then add N,N'-carbonyldiimidazole and carry out the activation reaction at room temperature. After the reaction is complete, an activated cellulose suspension is obtained.

[0020] Preferably, in step A3, the mass ratio of the microcrystalline cellulose to N,N'-carbonyldiimidazole is 1:0.8-1.2;

[0021] Preferably, in step A3, the activation reaction takes 3-6 hours.

[0022] A4. Add the guanidine intermediate prepared in step A2 to the activated cellulose suspension prepared in step A3, mix well, add triethylamine, raise the reaction temperature to carry out the cross-linking reaction, after the reaction is completed, cool, pour into anhydrous ethanol, precipitate, filter, collect the precipitate, wash and dry to obtain blank cellulose carrier.

[0023] Preferably, in step A4, the mass ratio between the guanidine intermediate and the microcrystalline cellulose in step A3 is 1:10-15;

[0024] Preferably, in step A4, the molar ratio between the guanidine intermediate and triethylamine is 1:1.0-1.5;

[0025] Preferably, in step A4, the crosslinking reaction temperature is 40-50°C, and the crosslinking reaction time is 18-24 hours.

[0026] This invention also provides a method for preparing a preventive drug formulation for porcine reproductive and respiratory syndrome, specifically comprising the following steps:

[0027] S1. Place the blank cellulose carrier in a flask, add anhydrous ethanol, stir at 300 rpm, and after 1-2 hours, filter, wash and dry to obtain the pretreated blank cellulose carrier.

[0028] S2. Accurately weigh tylosin tartrate and dissolve it in hydrochloric acid aqueous solution. Add the pretreated blank cellulose carrier prepared in step S1 to the reaction system and place it in a constant temperature shaker. Shake at 25℃ and 150 rpm under light-protected conditions. After 4-6 hours, the loading is completed. Filter, collect the solid, wash and dry to obtain drug carrier nanoparticles.

[0029] Preferably, in step S2, the mass concentration of tartrate tylosin in hydrochloric acid aqueous solution is 8-12 mg / mL;

[0030] S3. Under light-protected conditions, add anhydrous ethanol to a beaker, then add triethyl citrate and talc powder in sequence. After mixing evenly, dissolve the methacrylic acid-ethyl acrylate copolymer in deionized water and add it to the reaction system. Continue stirring for 60-80 minutes. After mixing evenly, a blocking solution is obtained.

[0031] S4. Start the fluidized bed, add the drug carrier nanoparticles prepared in step S2 into the fluidized bed material chamber, turn on the fan and adjust the fan speed to 30-40Hz, add the sealing liquid prepared in step S3 into the feed pump, and atomize and spray it onto the surface of the drug carrier nanoparticles at a uniform speed of 2.5g / min. After the sealing liquid is sprayed, turn off the feed pump and continue to maintain fluidization. After the coating treatment is completed, transfer it to a vacuum drying oven and set the aging conditions: aging temperature of 40-50℃, aging time of 18-24h. After aging is completed, cool to room temperature and pass through a 60-mesh sieve to obtain the drug formulation.

[0032] Preferably, in step S4, the ratio of the drug carrier nanoparticles to the blocking liquid is 1g:5-10mL.

[0033] The beneficial effects achieved by this invention are as follows:

[0034] This invention provides a preventative drug formulation for porcine reproductive and respiratory syndrome (PRRS) and its preparation method. The invention utilizes the technical characteristics of synthesizing a spirocyclic phosphate diacyl chloride intermediate from pentaerythritol and phosphorus oxychloride, and then reacting it with guanidine hydrochloride to construct a guanidine-functionalized crosslinking agent. This results in a guanidine-based intermediate with a rigid spirocyclic structure, providing stable crosslinking sites and spatial framework support for subsequent cellulose crosslinking. This achieves the fundamental technical effect of constructing a three-dimensional porous network carrier framework. Furthermore, the invention employs N,N'-carbonyldiimidazole to activate the primary hydroxyl groups of cellulose, and then reacts with the guanidine-based intermediate in a monosubstitution reaction to form a carbamate covalent bond. This allows for precise crosslinking of cellulose segments through pH-responsive chemical bonds. This study achieved the technical effect of preparing a pH-responsive blank cellulose porous carrier with gastric acid stability and intestinal fluid hydrolysis characteristics. The technical feature of the rigid spirocyclic phosphate backbone formed by cross-linking synergistically constructing a hierarchical porous structure with carbamate bonds increases the specific surface area and loading sites of the carrier, improving the dispersion uniformity and binding strength of tylosin tartrate in the carrier. This achieves the technical effects of avoiding drug aggregation, reducing the use of binders and dispersants, and improving drug loading stability. Through the intrinsic reaction mechanism of protonation inhibition of hydrolysis in acidic gastric fluid and deprotonation triggering hydrolysis in neutral intestinal fluid, the drug maintains structural stability and is not released in the stomach, while remaining stable in the intestines... The technology achieves stable and sustained release through gradual hydrolysis of the carrier skeleton, realizing intestinal-targeted sustained release of drugs at the carrier structure level. It utilizes a fluidized bed coating technique, employing a methacrylate-ethyl acrylate copolymer combined with triethyl citrate and talc to prepare an enteric coating solution. This forms a dense, flexible, and gastric acid-resistant enteric protective film on the carrier surface, further blocking gastric acid erosion, preventing sudden drug release in the stomach, and simultaneously protecting the structural integrity of the internal carrier and drug. The technology employs a dual sustained-release synergistic feature: pH-responsive dissolution of the enteric coating layer and pH-responsive hydrolysis of the internal cross-linked cellulose carrier. This allows the outer enteric membrane to control the timing of drug release initiation, while the internal... The porous framework controls the gradient sustained-release mode of drug release rate, achieving the technical effects of optimizing drug release curve and prolonging drug intestinal absorption period. The rigid three-dimensional framework of cross-linked cellulose carrier enhances mechanical strength and anti-solvent and anti-hygroscopic properties, avoiding problems such as disintegration, moisture absorption, and deformation of the carrier during preparation, storage, and coating, thus improving the processing and storage stability of the formulation. The enteric coating's dual protection of light-blocking, water-blocking, and oxygen-blocking effects, combined with the cross-linked carrier's encapsulation and confinement effect on the drug, reduces the degradation risk of tylosin tartrate caused by environmental factors such as light, heat, and humidity, and significantly improves the stability of the formulation under high temperature, high humidity, and strong light conditions. Attached Figure Description

[0035] Figure 1 The graphs show the stability results of the pharmaceutical formulations prepared in Examples 1-3 and Comparative Examples 1-2 of this invention.

[0036] Figure 2 The graph shows the in vitro release performance results of the pharmaceutical formulations prepared in Examples 1-3 and Comparative Examples 1-2 of this invention.

[0037] The accompanying drawings are provided to further illustrate the invention and form part of the specification. They are used together with the embodiments of the invention to explain the invention and do not constitute a limitation thereof. Detailed Implementation

[0038] The technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings of the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0039] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to this invention. The preferred embodiments and materials described herein are for illustrative purposes only and do not limit the scope of this application.

[0040] Unless otherwise specified, the experimental methods used in the following examples are conventional methods; unless otherwise specified, the experimental materials and test strains used in the following examples were purchased from commercial channels.

[0041] Example 1

[0042] This embodiment provides a preventive drug formulation for porcine reproductive and respiratory syndrome. The drug formulation uses tartrate as the active substance, which is loaded onto a blank cellulose carrier to obtain drug carrier nanoparticles. The nanoparticles are then coated with a blocking solution, which is obtained by dispersing methacrylate-ethyl acrylate copolymer, triethyl citrate and talc in deionized water.

[0043] The raw materials for preparing the pharmaceutical formulation include the following components in parts by weight: 60 parts drug carrier nanoparticles, 15 parts methacrylate-ethyl acrylate copolymer, 3 parts triethyl citrate, and 1 part talc.

[0044] In the drug carrier nanoparticles, the mass ratio of tartrate tylosin to blank cellulose carrier is 1:1;

[0045] The method for preparing a blank cellulose carrier specifically includes the following steps:

[0046] A1. Under a nitrogen atmosphere, 30 mL of anhydrous acetonitrile was added to a three-necked flask. The mixture was stirred (300 rpm) and the system was cooled to 0°C. 4.0 mL of phosphorus oxychloride was slowly added dropwise to the anhydrous acetonitrile. After the addition was complete, the temperature was raised to 80°C for a first reflux reaction. The reaction was carried out for 60 min. After the reaction was completed, 1.0 g of pentaerythritol was accurately weighed and added to the reaction system in three portions. At the same time, 4.6 mL of triethylamine was added dropwise to the reaction system at a rate of 1 mL / min. After mixing thoroughly, the temperature was maintained at 80°C, and a second reflux reaction was carried out at a rate of 300 rpm for 12 h. After the reaction was completed, excess solvent and unreacted reactants were removed by vacuum distillation. Hexane was added to the residue and stirred. The residue was filtered to remove the triethylamine hydrochloride precipitate. The filtrate was concentrated to dryness under vacuum to obtain the spirocyclic phosphate diacyl chloride intermediate.

[0047] A2. Under nitrogen protection, 1.4 g of the spirocyclic phosphate diacyl chloride intermediate prepared in step A1 was dissolved in 20 mL of anhydrous DMF. 1.1 g of guanidine hydrochloride was added to the reaction system, and the mixture was stirred at 300 rpm until the reactants were completely dissolved. Then, 2.9 mL of triethylamine was added, and the reaction temperature was raised to 60 °C to carry out the substitution reaction. After reacting for 10 h under light-protected conditions, the reaction system was allowed to cool naturally to room temperature. The reaction system was then poured into ice water and stirred at 500 rpm. After the precipitate was formed, it was filtered. The filter cake was washed three times with deionized water and anhydrous ethanol, and then collected. The filter cake was dried under vacuum at 40 °C for 12 h to obtain the guanidine intermediate.

[0048] A3. Accurately weigh 10g of microcrystalline cellulose and place it in a flask. Add 150mL of anhydrous DMF and allow it to swell at 25℃ and 200rpm. After 2 hours, add 8g of N,N'-carbonyldiimidazole to the reaction system in three portions. Keep the system at room temperature and continue stirring to carry out the activation reaction. After 6 hours of reaction, an activated cellulose suspension is obtained.

[0049] A4. Add 0.8 g of the guanidine intermediate prepared in step A2 to the activated cellulose suspension prepared in step A3. After mixing evenly at 300 rpm, add 0.3 g of triethylamine to the reaction system and stir continuously for 30 min. Then raise the reaction temperature to 40℃ and carry out the cross-linking reaction by stirring continuously in a light-protected environment for 24 h. After the reaction is completed, after the reaction system cools naturally to room temperature, slowly pour the reaction system into anhydrous ethanol and stir at 300 rpm for 30 min to precipitate. Filter the precipitate and wash it repeatedly with anhydrous ethanol and deionized water three times in sequence. After freeze-drying the precipitate, a blank cellulose carrier is obtained.

[0050] This invention also provides a method for preparing a preventive drug formulation for porcine reproductive and respiratory syndrome, specifically comprising the following steps:

[0051] S1. Take 10g of blank cellulose carrier and place it in a flask. Add 50mL of anhydrous ethanol and stir at 300rpm. After 1h, filter and wash repeatedly with deionized water 3 times. Place it in a vacuum drying oven and dry it at 40℃ for 12h to obtain the pretreated blank cellulose carrier.

[0052] S2. Accurately weigh 10g of tylosin tartrate and place it in an Erlenmeyer flask. Add 100mL of 0.1mol / L hydrochloric acid aqueous solution to completely dissolve the tylosin tartrate. Then, add the pretreated blank cellulose carrier prepared in step S1 to the reaction system. Place the system in a constant temperature shaker and shake at 25℃ and 150rpm under light-protected conditions for 6 hours. After that, the loading is complete. Filter the solid, collect it, wash it with deionized water, and vacuum dry it at 30℃ for 12 hours to obtain drug carrier nanoparticles.

[0053] S3. Under light-protected conditions, add 20 mL of anhydrous ethanol to a beaker, then add 0.3 g of triethyl citrate and 0.1 g of talc powder in sequence. Stir at 300 rpm at room temperature until the mixture is homogeneous. Then, accurately weigh 1.5 g of methacrylate-ethyl acrylate copolymer, dissolve it in 30 mL of deionized water, add it to the reaction system, and continue stirring for 60 min. After mixing evenly, the blocking solution is obtained.

[0054] S4. Start the fluidized bed and set the inlet air temperature to 35℃. Accurately weigh 6g of the drug carrier nanoparticles prepared in step S2 and add them to the fluidized bed material chamber. Turn on the fan and adjust the fan speed to 35Hz. Maintain fluidization preheating for 5 minutes. Add 50mL of the blocking liquid prepared in step S3 to the feed pump and atomize it at a uniform speed of 2.5g / min onto the surface of the drug carrier nanoparticles. After the blocking liquid is sprayed, turn off the feed pump and continue to maintain fluidization for 5 minutes. After the coating treatment is completed, transfer it to a vacuum drying oven and set the aging conditions: aging temperature 40℃, aging time 24h. After aging is completed, cool to room temperature and pass through a 60-mesh sieve to obtain the drug formulation.

[0055] Example 2

[0056] This embodiment provides a preventive drug formulation for porcine reproductive and respiratory syndrome. The drug formulation uses tartrate as the active substance, which is loaded onto a blank cellulose carrier to obtain drug carrier nanoparticles. The nanoparticles are then coated with a blocking solution, which is obtained by dispersing methacrylate-ethyl acrylate copolymer, triethyl citrate and talc in deionized water.

[0057] The raw materials for preparing the pharmaceutical formulation include the following components in parts by weight: 70 parts drug carrier nanoparticles, 18 parts methacrylate-ethyl acrylate copolymer, 4 parts triethyl citrate, and 2 parts talc.

[0058] In the drug carrier nanoparticles, the mass ratio of tartrate tylosin to blank cellulose carrier is 1:2.

[0059] The method for preparing a blank cellulose carrier specifically includes the following steps:

[0060] A1. Under a nitrogen atmosphere, 30 mL of anhydrous acetonitrile was added to a three-necked flask. The mixture was stirred (300 rpm) and the system was cooled to 0°C. 6.7 mL of phosphorus oxychloride was slowly added dropwise to the anhydrous acetonitrile. After the addition was complete, the temperature was raised to 80°C for a first reflux reaction. The reaction was carried out for 60 min. After the reaction was completed, 2.0 g of pentaerythritol was accurately weighed and added to the reaction system in three portions. At the same time, 9.0 mL of triethylamine was added dropwise to the reaction system at a rate of 1 mL / min. After mixing thoroughly, the temperature was maintained at 90°C, and a second reflux reaction was carried out at a rate of 300 rpm for 8 h. After the reaction was completed, excess solvent and unreacted reactants were removed by vacuum distillation. Hexane was added to the residue and stirred. The residue was filtered to remove the triethylamine hydrochloride precipitate. The filtrate was concentrated to dryness under vacuum to obtain the spirocyclic phosphate diacyl chloride intermediate.

[0061] A2. Under nitrogen protection, 2.8 g of the spirocyclic phosphate diacyl chloride intermediate prepared in step A1 was dissolved in 20 mL of anhydrous DMF. 2.0 g of guanidine hydrochloride was added to the reaction system, and the mixture was stirred at 300 rpm until the reactants were completely dissolved. Then, 5.5 mL of triethylamine was added, and the reaction temperature was raised to 65 °C to carry out the substitution reaction. After reacting for 8 h under light-protected conditions, the reaction system was allowed to cool naturally to room temperature. The reaction system was then poured into ice water and stirred at 500 rpm. After the precipitate was formed, it was filtered. The filter cake was washed three times with deionized water and anhydrous ethanol, and then collected. The filter cake was dried under vacuum at 40 °C for 12 h to obtain the guanidine intermediate.

[0062] A3. Accurately weigh 12g of microcrystalline cellulose and place it in a flask. Add 150mL of anhydrous DMF and allow it to swell at 25℃ and 200rpm. After 3h, add 12g of N,N'-carbonyldiimidazole to the reaction system in three portions. Keep the mixture at room temperature and continue stirring to carry out the activation reaction. After 4.5h of reaction, an activated cellulose suspension is obtained.

[0063] A4. Add 1.0 g of the guanidine intermediate prepared in step A2 to the activated cellulose suspension prepared in step A3. After mixing evenly at 300 rpm, add 0.5 g of triethylamine to the reaction system and stir continuously for 30 min. Then raise the reaction temperature to 45°C and carry out the cross-linking reaction by stirring continuously in a light-protected environment for 21 h. After the reaction is completed, let the reaction system cool naturally to room temperature, then slowly pour the reaction system into anhydrous ethanol and stir at 300 rpm for 30 min to precipitate. Filter the precipitate and wash it repeatedly with anhydrous ethanol and deionized water three times in sequence. After freeze-drying the precipitate, a blank cellulose carrier is obtained.

[0064] This invention also provides a method for preparing a preventive drug formulation for porcine reproductive and respiratory syndrome, specifically comprising the following steps:

[0065] S1. Take 10g of blank cellulose carrier and place it in a flask. Add 50mL of anhydrous ethanol and stir at 300rpm. After 1.5h, filter and wash repeatedly with deionized water 3 times. Place it in a vacuum drying oven and dry it at 40℃ for 12h to obtain the pretreated blank cellulose carrier.

[0066] S2. Accurately weigh 5g of tartrate tylosin and place it in an Erlenmeyer flask. Add 100mL of 0.1mol / L hydrochloric acid aqueous solution to completely dissolve the tartrate tylosin. Then, add the pretreated blank cellulose carrier prepared in step S1 to the reaction system. Place the system in a constant temperature shaker and shake at 25℃ and 150rpm under light-protected conditions for 5h. After that, the loading is complete. Filter the solid, collect it, wash it with deionized water, and vacuum dry it at 30℃ for 12h to obtain drug carrier nanoparticles.

[0067] S3. Under light-protected conditions, add 20 mL of anhydrous ethanol to a beaker, then add 0.4 g of triethyl citrate and 0.2 g of talc powder in sequence. Stir at 300 rpm at room temperature until the mixture is homogeneous. Then, accurately weigh 1.8 g of methacrylate-ethyl acrylate copolymer, dissolve it in 30 mL of deionized water, add it to the reaction system, and continue stirring for 60 min. After mixing evenly, the blocking solution is obtained.

[0068] S4. Start the fluidized bed and set the inlet air temperature to 35℃. Accurately weigh 7g of the drug carrier nanoparticles prepared in step S2 and add them to the fluidized bed material chamber. Turn on the fan and adjust the fan speed to 30Hz. Maintain fluidization preheating for 5 minutes. Add 50mL of the blocking liquid prepared in step S3 to the feed pump and atomize it at a uniform speed of 2.5g / min onto the surface of the drug carrier nanoparticles. After the blocking liquid is sprayed, turn off the feed pump and continue to maintain fluidization for 5 minutes. After the coating treatment is completed, transfer it to a vacuum drying oven and set the aging conditions: aging temperature 45℃, aging time 21h. After aging is completed, cool to room temperature and pass through a 60-mesh sieve to obtain the drug formulation.

[0069] Example 3

[0070] This embodiment provides a preventive drug formulation for porcine reproductive and respiratory syndrome. The drug formulation uses tartrate as the active substance, which is loaded onto a blank cellulose carrier to obtain drug carrier nanoparticles. The nanoparticles are then coated with a blocking solution, which is obtained by dispersing methacrylate-ethyl acrylate copolymer, triethyl citrate and talc in deionized water.

[0071] The raw materials for preparing the pharmaceutical formulation include the following components in parts by weight: 65 parts drug carrier nanoparticles, 20 parts methacrylate-ethyl acrylate copolymer, 5 parts triethyl citrate, and 3 parts talc.

[0072] In the drug carrier nanoparticles, the mass ratio of tartrate tylosin to blank cellulose carrier is 3:4.

[0073] The method for preparing a blank cellulose carrier specifically includes the following steps:

[0074] A1. Under a nitrogen atmosphere, 30 mL of anhydrous acetonitrile was added to a three-necked flask. The mixture was stirred (300 rpm) and the system was cooled to 0°C. 8.1 mL of phosphorus oxychloride was slowly added dropwise to the anhydrous acetonitrile. After the addition was complete, the temperature was raised to 80°C for a first reflux reaction. The reaction was carried out for 60 min. After the reaction was completed, 3.0 g of pentaerythritol was accurately weighed and added to the reaction system in three portions. At the same time, 14.1 mL of triethylamine was added dropwise to the reaction system at a rate of 1 mL / min. After mixing thoroughly, the temperature was maintained at 85°C, and a second reflux reaction was carried out at a rate of 300 rpm for 10 h. After the reaction was completed, excess solvent and unreacted reactants were removed by vacuum distillation. Hexane was added to the residue and stirred. The residue was filtered to remove the triethylamine hydrochloride precipitate. The filtrate was concentrated to dryness under reduced pressure to obtain the spirocyclic phosphate diacyl chloride intermediate.

[0075] A2. Under nitrogen protection, 3.8 g of the spirocyclic phosphate diacyl chloride intermediate prepared in step A1 was dissolved in 20 mL of anhydrous DMF. 2.5 g of guanidine hydrochloride was added to the reaction system, and the mixture was stirred at 300 rpm until the reactants were completely dissolved. Then, 7.1 mL of triethylamine was added, and the reaction temperature was raised to 70 °C to carry out the substitution reaction. After reacting for 6 h under light-protected conditions, the reaction system was allowed to cool naturally to room temperature. The reaction system was then poured into ice water and stirred at 500 rpm. After the precipitate was formed, it was filtered. The filter cake was washed three times with deionized water and anhydrous ethanol, and then collected. The filter cake was dried under vacuum at 40 °C for 12 h to obtain the guanidine intermediate.

[0076] A3. Accurately weigh 15g of microcrystalline cellulose and place it in a flask. Add 150mL of anhydrous DMF and allow it to swell at 25℃ and 200rpm. After 4h, add 18g of N,N'-carbonyldiimidazole to the reaction system in three portions. Keep the system at room temperature and continue stirring to carry out the activation reaction. After 3h of reaction, an activated cellulose suspension is obtained.

[0077] A4. Add 1.2g of the guanidine intermediate prepared in step A2 to the activated cellulose suspension prepared in step A3. After mixing evenly at 300rpm, add 0.7g of triethylamine to the reaction system and stir continuously for 30min. Then raise the reaction temperature to 50℃ and carry out the cross-linking reaction by stirring continuously in a light-protected environment for 18h. After the reaction is completed, let the reaction system cool naturally to room temperature, then slowly pour the reaction system into anhydrous ethanol and stir at 300rpm for 30min to precipitate. Filter the precipitate and wash it repeatedly with anhydrous ethanol and deionized water three times in sequence. After freeze-drying the precipitate, a blank cellulose carrier is obtained.

[0078] This invention also provides a method for preparing a preventive drug formulation for porcine reproductive and respiratory syndrome, specifically comprising the following steps:

[0079] S1. Take 10g of blank cellulose carrier and place it in a flask. Add 50mL of anhydrous ethanol and stir at 300rpm. After 2h, filter and wash repeatedly with deionized water 3 times. Place it in a vacuum drying oven and dry under vacuum at 40℃ for 12h to obtain the pretreated blank cellulose carrier.

[0080] S2. Accurately weigh 7.5g of tylosin tartrate and place it in an Erlenmeyer flask. Add 100mL of 0.1mol / L hydrochloric acid aqueous solution to completely dissolve the tylosin tartrate. Then, add the pretreated blank cellulose carrier prepared in step S1 to the reaction system. Place the system in a constant temperature shaker and shake at 25℃ and 150rpm under light-protected conditions for 4 hours. After that, the loading is complete. Filter the solid, collect it, wash it with deionized water, and vacuum dry it at 30℃ for 12 hours to obtain drug carrier nanoparticles.

[0081] S3. Under light-protected conditions, add 20 mL of anhydrous ethanol to a beaker, then add 0.5 g of triethyl citrate and 0.3 g of talc powder in sequence. Stir at 300 rpm at room temperature until the mixture is homogeneous. Then, accurately weigh 2.0 g of methacrylate-ethyl acrylate copolymer, dissolve it in 30 mL of deionized water, add it to the reaction system, and continue stirring for 60 min. After mixing evenly, the blocking solution is obtained.

[0082] S4. Start the fluidized bed and set the inlet air temperature to 35℃. Accurately weigh 6.5g of the drug carrier nanoparticles prepared in step S2 and add them to the fluidized bed material chamber. Turn on the fan and adjust the fan speed to 40Hz. Maintain fluidization preheating for 5 minutes. Add 50mL of the blocking liquid prepared in step S3 to the feed pump and atomize it at a uniform speed of 2.5g / min onto the surface of the drug carrier nanoparticles. After the blocking liquid is sprayed, turn off the feed pump and continue fluidization for 5 minutes. After the coating treatment is completed, transfer it to a vacuum drying oven and set the aging conditions: aging temperature 50℃, aging time 18h. After aging is completed, cool to room temperature and pass through a 60-mesh sieve to obtain the drug formulation.

[0083] Comparative Example 1

[0084] This comparative example provides a pharmaceutical preparation and its preparation method. The only difference between this example and Example 1 is that the pharmaceutical preparation uses a blank cellulose carrier to load tartrate tylosin instead of a blocking solution for coating. The other components and their contents are the same as in Example 1.

[0085] Comparative Example 2

[0086] This comparative example provides a pharmaceutical preparation and its preparation method. The only difference between this example and Example 1 is that, in the preparation method of the blank cellulose carrier, the cross-linking reaction in step A4 is omitted during the preparation of the blank cellulose carrier. Uncross-linked cellulose is directly used as a carrier to load tartrate tylosin, and no blocking liquid coating treatment is performed. The remaining components and component contents are the same as in Example 1.

[0087] Experimental Example

[0088] This experiment tests the stability of the pharmaceutical preparations prepared in Examples 1-3 and Comparative Examples 1-2. The pharmaceutical preparations prepared in Examples 1-3 and Comparative Examples 1-2 were individually packaged in light-proof sealed bags and placed in a desiccator for equilibration for 24 hours (25°C, RH 60%±5%) to obtain pretreated samples for later use.

[0089] ① High-temperature stability test: Take the pretreated samples (Examples 1-3, Comparative Examples 1-2), take 3 parallel samples for each group, 2g each, spread them evenly in a petri dish, place the petri dish in a constant temperature and humidity incubator preheated to 60℃, record the placement time, and at the same time point on the 10th day, take out each group of parallel samples, quickly place them in a desiccator to cool to room temperature (25℃, equilibrate for 30min) to avoid sudden temperature changes that may cause changes in the formulation structure, observe the appearance, and test the TAT content;

[0090] ② High humidity stability test: Take the pretreated samples (Examples 1-3, Comparative Examples 1-2), take 3 parallel samples from each group, 2g each, spread them evenly in a petri dish, place a petri dish containing saturated potassium chloride solution (the solution volume occupies 2 / 3 of the petri dish volume) at the bottom of the incubator, ensuring that the solution does not overflow, place the sample petri dish on the support and seal the incubator, record the placement time (day 0), maintain the temperature at 25℃ and RH at 92.5%, at the same time point on day 10, take out each group of parallel samples, gently wipe the water droplets on the sample surface with filter paper (to avoid the sample absorbing too much water and causing detection deviation), after equilibration for 30 minutes, observe the appearance and test the TAT content;

[0091] ③ Strong light stability test: Take the pretreated samples (Examples 1-3, Comparative Examples 1-2), take 3 parallel samples for each group, 2g each, spread them evenly in a petri dish, place the petri dish in a strong light stability test chamber, adjust the light intensity to 4500lx, record the placement time, record the light intensity and temperature every 2 hours, and ensure that the light intensity fluctuation is ≤±200lx and the temperature fluctuation is ≤±0.5℃. At the same time point on the 10th day, take out each group of parallel samples, put them into a light-proof sealed bag immediately, equilibrate for 30 minutes, observe the appearance, and test the TAT content;

[0092] Figure 1 The stability results of the pharmaceutical formulations prepared in Examples 1-3 and Comparative Examples 1-2 of this invention are shown in the following table: Other appearance observation results are shown in the following table:

[0093]

[0094] The results above show that Examples 1-3 exhibit excellent stability under high-temperature conditions. The appearance of the formulation remained unchanged, consistently maintaining a white, uniform powder without discoloration or clumping. The TAT content decreased by only 3.3% to 4.1%, far lower than that of Comparative Examples 1 and 2. The enteric coating of methacrylate-ethyl acrylate copolymer (MEC) has good high-temperature resistance, and will not melt or break at 60°C. It can form a dense physical barrier, preventing heat conduction to the carrier interior and avoiding TAT hydrolysis and degradation due to high temperatures. The urethane covalent bonds (-OC(=O)-N-) formed by guanidinyl-spirocyclic phosphate crosslinking have excellent thermal stability and will not break at high temperatures. The three-dimensional crosslinked cellulose skeleton structure remains dense and intact, stably supporting TAT and preventing TAT exposure and degradation due to carrier disintegration. Comparative Example 1 showed a significant decrease in stability under high temperature conditions: slight discoloration (pale yellow) and a 9.9% decrease in TAT content. Lacking MEC enteric coating and without physical barrier protection, the high temperature directly affected the TAT on the surface and inside the carrier, leading to the destruction of the TAT molecular structure and slight degradation. However, due to the presence of a cross-linked cellulose backbone structure, the carrier did not disintegrate, and the TAT was not fully exposed. Therefore, the degree of degradation was relatively controllable, and no serious exceedance of standards was observed. Comparative Example 2 showed the worst stability under high temperature conditions, with obvious discoloration and slight clumping, and a 17.7% decrease in TAT content. Lacking enteric coating, the high temperature directly affected the TAT, accelerating its degradation. Lacking a carbamate cross-linked structure, the cellulose carrier was an uncross-linked linear structure, which was prone to chain segment contraction and aggregation at high temperatures. The slight clumping of the carrier led to a large exposure of TAT, significantly accelerating the degradation rate.

[0095] Experiment Example 2

[0096] This experiment tested the in vitro release performance of Examples 1-3 and Comparative Examples 1-2. The drug formulations prepared in Examples 1-3 and Comparative Examples 1-2 were individually packaged in light-proof sealed bags, labeled with sample name and preparation date, and placed in a desiccator for equilibration for 24 hours. Simulated gastric fluid was prepared (according to the Chinese Veterinary Pharmacopoeia, 3.2 mL of hydrochloric acid was added, 2.0 g of sodium chloride was added, and the volume was adjusted to 1000 mL with deionized water and stirred evenly; the pH value was calibrated to 1.2 using a pH meter; the solution was filtered through a 0.22 μm organic filter membrane, ultrasonically degassed for 30 min to remove air bubbles, and then stored in the dark). The entire test was conducted in a light-proof environment (the dissolution apparatus was wrapped in a black light-proof cloth, and sampling and testing were completed in a light-proof operating table). The temperature of the in vivo gastrointestinal tract was simulated (37°C). The release was first performed in the simulated gastric fluid stage, and then in the simulated intestinal fluid stage. Sampling was strictly performed according to the set time points to ensure that the drug release process was consistent with the in vivo gastrointestinal transport process.

[0097] Turn on the intelligent dissolution apparatus and set the parameters: temperature 37℃±0.5℃, paddle speed 50rpm, light-proof mode, preheat for 30 minutes to ensure the temperature inside the dissolution vessel is stable at 37℃. Add 900mL of simulated gastric fluid to each dissolution vessel, confirm there is no leakage, and continue stirring at a constant temperature for 10 minutes to ensure the medium temperature is uniform and there are no bubbles. Accurately weigh 0.5g of sample and add it to the simulated gastric fluid in each dissolution vessel, ensuring the sample is evenly dispersed in the medium. Start timing simultaneously, taking samples at 1h and 2h to test the TAT content in the system. After 2h, the simulated gastric fluid stage release is complete. Immediately proceed to the second stage of simulated intestinal fluid release. Without removing the sample and medium from the dissolution vessel, directly adjust the pH of the medium to 6.8 to enter the intestinal release stage. After the values ​​are adjusted, start timing (recorded as 0h for intestinal release, corresponding to 3h for overall release). Continue stirring at a constant temperature in the dark to carry out the intestinal fluid stage of release, continuing for 6h, until the overall release time reaches 8h. Take samples at the set time points (3h, 4h, 6h, 8h), calculate the actual concentration of TAT in the dissolution solution at each time point, and calculate the cumulative release rate according to the following formula:

[0098] Cumulative release rate ;

[0099] Among them, C n : Actual concentration of TAT in the dissolution solution at the nth time point (μg / mL); Vtotal: Total volume of medium in the dissolution vessel; C i : Actual concentration (μg / mL) of TAT in the dissolution solution at each sampling time point before the nth time point; V 取 : Sampling volume (mL); m: Sample mass (g); w: Actual TAT content (%) in the sample, i.e., the measured TAT content on day 0 of the stability test (Examples 1-3 and Comparative Examples 1-2 were calibrated to 100.0%, and the measured deviation was ≤ ±2.0%).

[0100] Figure 2The figures show the in vitro release performance results of the drug formulations prepared in Examples 1-3 and Comparative Examples 1-2 of this invention. As shown in the figures, the prophylactic drug formulations for porcine reproductive and respiratory syndrome prepared in Examples 1-3 all exhibited ideal gastrointestinal targeted sustained-release characteristics. In a simulated gastric fluid (pH 1.2) environment, the cumulative release rate after 2 hours was only 2.8%~3.5%, far below the qualified standard of 5%, achieving zero burst release in the stomach. This effectively protects tylosin tartrate (TAT) from being destroyed by the gastric environment. The core benefit is the dense physical barrier formed by the non-dissolving outer methacrylate-ethyl acrylate copolymer (MEC) enteric coating under acidic conditions, and the synergistic effect of the internal carbamate cross-links undergoing N protonation under acidic conditions, remaining non-hydrolyzed, and maintaining the integrity of the skeleton. After entering a simulated intestinal fluid (pH 6.8) environment... The enteric coating dissolves rapidly, and the cross-linked bonds are gradually deprotonated and hydrolyzed. TAT is released steadily and slowly from the multi-level pores of the three-dimensional cross-linked framework, achieving full release of TAT, ensuring sufficient intestinal absorption and sustained efficacy. In contrast, Comparative Example 1 (without enteric coating, but with cross-linked structure) showed a large burst release in the stomach after 2 hours, and after 4 hours in the intestinal fluid, the release was basically complete, with no true sustained-release effect, lacking the gastric protection of enteric coating. Comparative Example 2 showed a severe burst release in the stomach after 2 hours, and after 4 hours in the intestinal fluid environment, it completely exhibited rapid-release characteristics, with no targeting or sustained-release value. It lacked the dual protection of enteric coating and cross-linked structure, and the carrier was prone to disintegration, leading to rapid exposure and dissolution of TAT. In summary, the synergistic effect of MEC enteric coating and urethane cross-linked cellulose carrier is the key to achieving gastric stability and intestinal targeted sustained release of the formulation.

[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.

[0102] The present invention and its embodiments have been described above. This description is not restrictive, and the accompanying drawings are only one embodiment of the present invention. The actual application is not limited to this. In conclusion, if those skilled in the art are inspired by this description and design similar methods and embodiments without departing from the spirit of the present invention, they should all fall within the protection scope of the present invention.

Claims

1. A preventive pharmaceutical preparation for porcine reproductive and respiratory syndrome, characterized in that: The pharmaceutical formulation uses tylosin tartrate as the active ingredient, which is loaded onto a blank cellulose carrier to obtain drug carrier nanoparticles. These nanoparticles are then coated with a blocking solution, which is obtained by dispersing methacrylic acid-ethyl acrylate copolymer, triethyl citrate, and talc in deionized water. The raw materials for preparing the pharmaceutical formulation include the following components in parts by weight: 60-70 parts drug carrier nanoparticles, 15-20 parts methacrylic acid-ethyl acrylate copolymer, 3-5 parts triethyl citrate, and 1-3 parts talc. The preparation method of the blank cellulose carrier specifically includes the following steps: A1. Under a nitrogen atmosphere, phosphorus oxychloride was dissolved in anhydrous acetonitrile, and the reaction temperature was increased to carry out a reflux reaction. After the reaction was completed, pentaerythritol and triethylamine were added, and the temperature was maintained to carry out a second reflux reaction. After the reaction was completed, the mixture was distilled under reduced pressure, and hexane was added to the residue and stirred. The mixture was filtered to remove the triethylamine hydrochloride precipitate. The filtrate was concentrated to dryness under reduced pressure to obtain the spirocyclic phosphate diacyl chloride intermediate. A2. Under a nitrogen atmosphere, the spirocyclic phosphate diacyl chloride intermediate prepared in step A1 was dissolved in anhydrous DMF, guanidine hydrochloride was added, and after mixing evenly, triethylamine was added. Under light-protected conditions, the reaction temperature was increased to carry out the substitution reaction. After the reaction was completed, the mixture was cooled, and the reaction system was poured into ice water. After the precipitate was formed, it was filtered, the filter cake was collected, and dried to obtain the guanidine intermediate. A3. Disperse microcrystalline cellulose in anhydrous DMF, allow it to swell fully for 2-4 hours, then add N,N'-carbonyldiimidazole and carry out the activation reaction at room temperature. After the reaction is complete, an activated cellulose suspension is obtained. A4. Add the guanidine intermediate prepared in step A2 to the activated cellulose suspension prepared in step A3, mix well, add triethylamine, raise the reaction temperature to carry out the cross-linking reaction, after the reaction is completed, cool, pour into anhydrous ethanol, precipitate, filter, collect the precipitate, wash and dry to obtain blank cellulose carrier.

2. The preventive pharmaceutical preparation for porcine reproductive and respiratory syndrome according to claim 1, characterized in that: In the drug carrier nanoparticles, the mass ratio between tartrate tylosin and blank cellulose carrier is 1:1-2.

3. The preventive pharmaceutical preparation for porcine reproductive and respiratory syndrome according to claim 2, characterized in that: In step A1, the molar ratio between phosphorus oxychloride and pentaerythritol is 4-6:1; the molar ratio between triethylamine and pentaerythritol is 4.4-4.6:1; the reaction temperature of the first reflux reaction is 80-90℃, the reaction time of the first reflux reaction is 30-60 min, the reaction temperature of the second reflux reaction is 80-90℃, and the reaction time of the second reflux reaction is 8-12 h.

4. The preventive pharmaceutical preparation for porcine reproductive and respiratory syndrome according to claim 3, characterized in that: In step A2, the molar ratio between the spirocyclic phosphate diacyl chloride intermediate and guanidine hydrochloride is 1:2.0-2.4; the molar ratio between the spirocyclic phosphate diacyl chloride intermediate and triethylamine is 1:4.0-4.5; the reaction temperature of the substitution reaction is 60-70℃, and the reaction time of the substitution reaction is 6-10h.

5. A preventive pharmaceutical preparation for porcine reproductive and respiratory syndrome according to claim 4, characterized in that: In step A3, the mass ratio of microcrystalline cellulose to N,N'-carbonyldiimidazole is 1:0.8-1.2; the activation reaction time is 3-6 hours.

6. The preventive pharmaceutical preparation for porcine reproductive and respiratory syndrome according to claim 5, characterized in that: In step A4, the mass ratio of the guanidine intermediate to the microcrystalline cellulose in step A3 is 1:10-15; the molar ratio of the guanidine intermediate to triethylamine is 1:1.0-1.5; the reaction temperature of the crosslinking reaction is 40-50℃, and the reaction time of the crosslinking reaction is 18-24h.

7. A method for preparing a prophylactic pharmaceutical preparation for porcine reproductive and respiratory syndrome according to any one of claims 1-6, characterized in that: Specifically, the steps include the following: S1. Place the blank cellulose carrier in a flask, add anhydrous ethanol, stir at 300 rpm, and after 1-2 hours, filter, wash and dry to obtain the pretreated blank cellulose carrier. S2. Accurately weigh tylosin tartrate and dissolve it in hydrochloric acid aqueous solution. Add the pretreated blank cellulose carrier prepared in step S1 to the reaction system and place it in a constant temperature shaker. Shake at 25℃ and 150 rpm under light-protected conditions. After 4-6 hours, the loading is completed. Filter, collect the solid, wash and dry to obtain drug carrier nanoparticles. S3. Under light-protected conditions, add anhydrous ethanol to a beaker, then add triethyl citrate and talc powder in sequence. After mixing evenly, dissolve the methacrylic acid-ethyl acrylate copolymer in deionized water and add it to the reaction system. Continue stirring for 60-80 minutes. After mixing evenly, a blocking solution is obtained. S4. Start the fluidized bed, add the drug carrier nanoparticles prepared in step S2 into the fluidized bed material chamber, turn on the fan, and adjust the fan speed to 30-40Hz. Add the sealing liquid prepared in step S3 to the feed pump and atomize it at a uniform speed of 2.5g / min onto the surface of the drug carrier nanoparticles. After the sealing liquid is sprayed, turn off the feed pump and continue to maintain fluidization. After the coating treatment is completed, transfer it to a vacuum drying oven and set the aging conditions: aging temperature of 40-50℃ and aging time of 18-24h. After aging is completed, cool to room temperature and pass through a 60-mesh sieve to obtain the drug formulation.

8. The method for preparing a preventive pharmaceutical preparation for porcine reproductive and respiratory syndrome according to claim 7, characterized in that: In step S2, the mass concentration of tartrate tylosin in hydrochloric acid aqueous solution is 8-12 mg / mL.

9. The method for preparing a preventive pharmaceutical preparation for porcine reproductive and respiratory syndrome according to claim 8, characterized in that: In step S4, the ratio of the drug carrier nanoparticles to the blocking liquid is 1g:5-10mL.

Images