Florfenicol derivative long-acting sustained release preparation and preparation process thereof

Abstract

The invention relates to the technical field of nano drug loading, in particular to a florfenicol derivative long-acting sustained release preparation and a preparation process thereof. The invention discloses a florfenicol-PEG-PLGA (poly (lactic-co-glycolic acid)-polyethylene glycol-poly (lactic-co-glycolic acid))-PLGA (poly (lactic-co-glycolic acid)) copolymer with a specific proportion, magnetic targeting microspheres, an antioxidant compound containing various components, a pH-responsive coating material and enzyme-responsive nanogel, wherein the derivative is formed by connecting florfenicol and 2-mercaptobenzothiazole; all the components are synergistic, so that long-acting slow release, targeting and intelligent drug release are realized, and the stability of the preparation is guaranteed. The method has outstanding advantages; the innovative components have a synergistic effect, can accurately target a diseased region, and intelligently release drugs in different environments; the composition can improve the drug concentration of diseased regions, enhance the curative effect, reduce the dosage and toxic and side effects, reduce the breeding cost, and have wide application prospects.

Description

Technical Field

[0001] The present invention relates to the technical field of nano drug delivery, in particular to a long-acting sustained-release preparation of a florfenicol derivative and a preparation process thereof. Background Art

[0002] The prevention and treatment of bacterial diseases has always been a key component in ensuring animal health and improving livestock production profitability. Florfenicol, a broad-spectrum antibacterial agent, is widely used in veterinary clinical practice, demonstrating excellent therapeutic efficacy against a variety of infectious diseases caused by Gram-positive and Gram-negative bacteria. However, traditional florfenicol formulations have numerous limitations in practical application.

[0003] Florfenicol has poor water solubility, which makes it difficult to disperse evenly during the formulation process, resulting in low bioavailability of the drug. After oral administration or injection to animals, the drug is not fully absorbed and cannot fully exert its antibacterial effect. It is often necessary to increase the dosage to maintain the therapeutic effect, which not only increases the breeding cost, but may also cause drug residue and drug resistance problems. Secondly, the drug release rate of traditional preparations is difficult to control. The drug quickly reaches a high concentration in the body and then drops rapidly. It is impossible to maintain an effective antibacterial concentration for a long time. Frequent administration is required, which brings great inconvenience to breeding production. Moreover, frequent and large-dose use will burden the liver and kidney functions of animals and affect their health.

[0004] While there are some improved florfenicol formulations on the market, most simply change the dosage form, such as powder injections or oral solutions, and fail to fundamentally address florfenicol's inherent flaws. Some so-called sustained-release formulations offer suboptimal sustained-release effects, with the inability to precisely control drug release, making it difficult to achieve effective therapeutic concentrations at the site of disease.

[0005] Biodegradable polymer materials, targeting technology, responsive materials, etc. are gradually applied to the field of pharmaceutical preparations. However, the synergistic application of these advanced technologies in the research and development of florfenicol preparations is still in the exploratory stage. Biodegradable polymer materials can achieve the slow release of drugs and prolong the drug action time, but how to improve their encapsulation efficiency and drug loading of florfenicol, and how to regulate their degradation rate and drug release rate, are still problems to be solved. Targeting technology can enable drugs to accurately reach the lesion site, improve drug efficacy, and reduce damage to normal tissues, but existing targeted microspheres are still insufficient in terms of stability, targeting efficiency, and combination mode with drugs. Responsive materials can achieve intelligent release of drugs according to changes in the body environment (such as pH value, enzyme concentration, etc.), but in florfenicol preparations, how to make responsive materials accurately respond and effectively control drug release while ensuring the stability and safety of the preparation has not yet been well solved.

[0006] Florfenicol is susceptible to oxidative degradation during storage and use, resulting in reduced drug activity. Existing antioxidant measures are often ineffective and fail to effectively protect the drug's active ingredients. Therefore, it is urgent to develop a long-acting, sustained-release formulation of a florfenicol derivative that can comprehensively address the existing issues of florfenicol and integrate long-term sustained-release, targeted delivery, intelligent responsive release, and antioxidant stability. Summary of the Invention

[0007] (1) Technical problems solved

[0008] In view of the deficiencies in the prior art, the present invention provides a long-acting sustained-release preparation of a florfenicol derivative and a preparation process thereof.

[0009] (2) Technical solution

[0010] A long-acting sustained-release preparation of a florfenicol derivative is composed of a florfenicol derivative, a novel biodegradable polymer carrier, intelligent targeting microspheres, an antioxidant enhancer, a pH-responsive coating material, and an enzyme-responsive nanogel; the florfenicol derivative is formed by linking florfenicol and 2-mercaptobenzothiazole via an amide bond, and the reaction process is as follows:

[0011]

[0012] The novel biodegradable polymer carrier is a poly(lactic acid-glycolic acid)-polyethylene glycol-poly(lactic acid-glycolic acid) triblock copolymer, wherein the molar ratio of lactic acid to glycolic acid in the poly(lactic acid-glycolic acid) segment is 75-85:15-25, and the number average molecular weight of the polyethylene glycol segment is 2000-3000 Da, accounting for 18%-28% by weight;

[0013] The smart targeting microspheres are made of magnetic nanoparticles Fe3O4 wrapped with polydopamine, which is then modified with the targeting ligand folic acid, accounting for 4%-7% by mass; the antioxidant enhancer is a complex of ferulic acid, vitamin C and epigallocatechin gallate, accounting for 3%-6% by mass; the pH-responsive coating material is dimethylaminoethyl methacrylate-methyl methacrylate copolymer, accounting for 6%-12% by mass; the enzyme-responsive nanogel is composed of poly N-isopropylacrylamide-acrylamide-methacrylic acid and a β-glucuronidase-responsive linker, accounting for 5%-10% by mass.

[0014] Preferably, the encapsulation efficiency of florfenicol derivatives in the novel biodegradable polymer carrier reaches 75%-90%, and the drug loading capacity is 12%-22%; by controlling the preparation temperature at 28-32°C, the stirring speed at 600-900 r / min, and the ultrasonic power at 80-120 W, the encapsulation efficiency and drug loading capacity can be precisely controlled.

[0015] Preferably, the magnetic nanoparticles Fe3O4 in the smart targeting microspheres have a particle size of 15-25 nm, a polydopamine layer thickness of 30-40 nm, and a folic acid modification amount of 0.2-0.4 mg per milligram of microspheres; when the external magnetic field strength is 0.1-0.3 T, the microspheres can quickly target the lesion site, and the targeting efficiency is improved by 30%-50%.

[0016] Preferably, the mass ratio of ferulic acid, vitamin C, and EGCG in the antioxidant synergist is 1.5-2.5:2.5-3.5:1-2; the complex can increase the antioxidant activity of the preparation by 40%-60% and significantly reduce the oxidative degradation of florfenicol derivatives.

[0017] Preferably, the glass transition temperature of the pH-responsive coating material is 32-38° C.; at a pH of 5-6, the coating swells and the drug release rate is 12%-22% per hour; at a pH of 7-8, the release rate is 2%-6% per hour.

[0018] Preferably, in the presence of β-glucuronidase, the enzyme-responsive nanogel has a response time of 3-6 hours, the gel structure is destroyed, the drug release is accelerated, and the release amount is increased by 30%-50%.

[0019] Preferably, a process for preparing a long-acting sustained-release preparation of a florfenicol derivative comprises the following steps:

[0020] Synthesis of Florfenicol Derivatives: Florfenicol and 2-mercaptobenzothiazole are reacted in dichloromethane at 22-28°C for 15-20 hours in the presence of a condensing agent, N,N'-dicyclohexylcarbodiimide, and a catalyst, 4-dimethylaminopyridine. The product is filtered, washed, and dried to obtain the product. The structure of the N,N'-dicyclohexylcarbodiimide is:

[0021]

[0022] The structure of the 4-dimethylaminopyridine is:

[0023]

[0024] Preparation of novel biodegradable polymer carrier solution: PLGA-PEG-PLGA was dissolved in acetone to prepare a solution with a mass fraction of 6%-9%;

[0025] Preparation of intelligent targeting microspheres: Fe3O4 was prepared by chemical coprecipitation, PDA was coated by self-polymerization, and FA was covalently linked to prepare microspheres;

[0026] Preparation of drug-loaded microspheres: Florfenicol derivatives and smart targeted microspheres were added to the carrier solution and prepared by the emulsification-solvent evaporation method at a stirring speed of 650-850 r / min, a temperature of 26-32°C, and a time of 4-5 hours;

[0027] Preparation of pH-responsive coating material solution: PDMAEMA-MMA is dissolved in ethanol to prepare a solution with a mass fraction of 4%-7%;

[0028] Preparation of enzyme-responsive nanogels: N-isopropylacrylamide, acrylamide, and methacrylic acid are used as monomers, a β-glucuronidase-responsive linker is added, and the reaction is carried out at 55-65°C for 3-5 hours under the action of an initiator;

[0029] Preparation molding: Fluidized bed coating of drug-loaded microspheres, followed by coating with pH-responsive coating material and enzyme-responsive nanogel, coating temperature 32-36°C, each coating time 2.5-3.5 hours.

[0030] Preferably, when synthesizing the florfenicol derivative, the molar ratio of florfenicol to 2-mercaptobenzothiazole is (1.1-1.3):1, the amount of DCC used is 1.2-1.4 times the molar amount of florfenicol, and the amount of DMAP used is 0.06-0.09 times the molar amount of florfenicol.

[0031] Preferably, in the preparation of drug-loaded microspheres, the mass ratio of florfenicol derivatives, smart targeting microspheres, and novel biodegradable polymer carriers is 1.5-2.5:0.8-1.5:10.

[0032] Preferably, a long-acting sustained-release preparation of a florfenicol derivative is used in the preparation of drugs for treating bacterial diseases in animals. The preparation can achieve long-acting sustained-release, targeted delivery and enzyme-triggered precise drug release of the florfenicol derivative, increase the drug concentration in the lesion site by 50%-80%, significantly enhance the therapeutic effect, reduce the drug dosage by 30%-50%, and reduce toxic side effects.

[0033] (3) Beneficial technical effects

[0034] Compared with the existing technology, the beneficial effects of the present invention are:

[0035] 1. By introducing a novel biodegradable polymer carrier, intelligent targeting microspheres, antioxidant enhancers, pH-responsive coating materials, and enzyme-responsive nanogels, a synergistic approach to multiple functions was achieved. The novel biodegradable polymer carrier not only improved the encapsulation efficiency and drug loading of florfenicol derivatives, but also achieved long-term sustained release of the drug, reducing the number of dosing times and alleviating animal stress responses. Intelligent targeting microspheres can precisely locate lesions under the guidance of an external magnetic field, increasing drug concentration in diseased tissues, enhancing therapeutic efficacy while reducing damage to normal tissues. Antioxidant enhancers effectively inhibited the oxidative degradation of florfenicol derivatives, ensuring drug stability during storage and use and extending the shelf life of the preparation.

[0036] 2. pH-responsive coatings and enzyme-responsive nanogels empower the formulation with intelligent drug release. The coating adjusts the drug release rate under varying pH conditions, accelerating release in the weakly acidic environment of inflammation while maintaining a relatively stable, low release rate in normal physiological conditions, thereby improving drug utilization efficiency. Enzyme-responsive nanogels, activated by specific enzymes at the lesion site, accelerate drug release, enabling precise treatment.

[0037] 3. This formulation increases drug concentration at the lesion site, significantly enhancing therapeutic efficacy, reducing drug dosage, and lowering the risk of drug residues and toxic side effects in animals. Furthermore, its long-lasting, sustained-release properties reduce dosing frequency, lowering labor intensity, and improving animal husbandry efficiency. This innovative formulation effectively addresses the challenges of traditional florfenicol formulations, providing a more efficient, safe, and convenient means of preventing and treating bacterial diseases in animals. It has broad market application prospects and significant economic and social benefits. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 It is a long-acting sustained-release preparation of florfenicol derivative and its preparation process production flow chart;

[0039] Figure 2 is a bar graph comparing the antioxidant performance improvement and targeting efficiency of the embodiment and the comparative example;

[0040] Figure 3 is the fitting curve of the remaining amount of the drug at different time points in the embodiment and the comparative example;

[0041] Figure 4 It is the nuclear magnetic resonance hydrogen spectrum of the florfenicol derivative proposed by the present invention. DETAILED DESCRIPTION

[0042] according to Figures 1 to 4 , the specific implementation of the present invention is as follows:

[0043] Example 1

[0044] Raw material preparation

[0045] Florfenicol derivatives: Weigh 10 g of florfenicol, 8.5 g of 2-mercaptobenzothiazole, 12 g of N,N'-dicyclohexylcarbodiimide (DCC), 0.8 g of 4-dimethylaminopyridine (DMAP), and an appropriate amount of dichloromethane.

[0046] A new biodegradable polymer carrier: poly(lactic acid-glycolic acid)-polyethylene glycol-poly(lactic acid-glycolic acid) (PLGA-PEG-PLGA), in which the molar ratio of lactic acid to glycolic acid in the PLGA segment is 80:20, the number average molecular weight of the PEG segment is 2500 Da, and the weight is 25g.

[0047] Smart targeting microspheres: magnetic nanoparticles Fe3O4 (particle size 20nm), dopamine, and folic acid in appropriate amounts.

[0048] Antioxidant synergists: Ferulic acid 2g, Vitamin C 3g, Epigallocatechin gallate (EGCG) 1.5g.

[0049] pH-responsive coating material: dimethylaminoethyl methacrylate-methyl methacrylate copolymer (PDMAEMA-MMA) 10 g.

[0050] Enzyme-responsive nanogel: N-isopropylacrylamide, acrylamide, methacrylic acid, β-glucuronidase-responsive linker, and appropriate amount of initiator.

[0051] Preparation process

[0052] Synthesis of Florfenicol Derivatives: Florfenicol and 2-mercaptobenzothiazole were added to dichloromethane, followed by DCC and DMAP, and the mixture was reacted at 25°C for 18 hours. After the reaction, the by-products were filtered out, washed with deionized water, and dried to obtain the Florfenicol Derivatives.

[0053] Preparation of novel biodegradable polymer carrier solution: PLGA-PEG-PLGA was dissolved in acetone to prepare a solution with a mass fraction of 8%.

[0054] Preparation of smart targeting microspheres: Fe3O4 was prepared by chemical coprecipitation, dispersed in a dopamine solution, coated with a polydopamine layer by self-polymerization, and folic acid was covalently linked to the polydopamine surface to obtain smart targeting microspheres.

[0055] Preparation of drug-loaded microspheres: Florfenicol derivatives and smart targeting microspheres were added to a novel biodegradable polymer carrier solution, stirred at 750 r / min, and reacted at 28°C for 4.5 hours. The drug-loaded microspheres were prepared by the emulsification-solvent evaporation method.

[0056] Preparation of pH-responsive coating material solution: PDMAEMA-MMA was dissolved in ethanol to prepare a solution with a mass fraction of 6%.

[0057] Preparation of enzyme-responsive nanogels: N-isopropylacrylamide, acrylamide, and methacrylic acid were used as monomers, β-glucuronidase-responsive linker and initiator were added, and the reaction was carried out at 60°C for 4 hours to prepare enzyme-responsive nanogels.

[0058] Preparation molding: The drug-loaded microspheres were placed in a fluidized bed coating device and first coated with a pH-responsive coating material solution at a coating temperature of 34°C for 3 hours; then coated with an enzyme-responsive nanogel under the same conditions.

[0059] Performance Testing

[0060] Encapsulation efficiency and drug loading: Determined by high performance liquid chromatography, the encapsulation efficiency was 82% and the drug loading was 18%.

[0061] Targeting efficiency: Under an external magnetic field of 0.2T, the targeting efficiency is 80%.

[0062] Antioxidant properties: As measured by DPPH free radical scavenging assay, the antioxidant activity was increased by 50%.

[0063] pH responsiveness: At a pH of 5.5, the drug release rate was 18% per hour; at a pH of 7.5, the release rate was 3% per hour.

[0064] Enzyme responsiveness: In the presence of β-glucuronidase, drug release increased by 40% after 6 hours.

[0065] Example 2

[0066] Raw material preparation

[0067] Florfenicol derivative: florfenicol 11g, 2-mercaptobenzothiazole 9.2g, DCC 13g, DMAP 0.9g, and appropriate amount of dichloromethane.

[0068] New biodegradable polymer carrier: PLGA-PEG-PLGA, the molar ratio of lactic acid to glycolic acid in the PLGA segment is 85:15, the number average molecular weight of the PEG segment is 3000Da, 28g.

[0069] Smart targeting microspheres: same as in Example 1.

[0070] Antioxidant synergists: Ferulic acid 2.5g, Vitamin C 3.5g, EGCG 2g.

[0071] pH responsive coating material: PDMAEMA-MMA 12g.

[0072] Enzyme-responsive nanogel: same as Example 1.

[0073] Preparation process

[0074] The method is basically the same as Example 1, except that: the reaction temperature for the synthesis of florfenicol derivatives is 28°C, and the reaction time is 20 hours; the stirring speed for the preparation of drug-loaded microspheres is 850 r / min, the temperature is 32°C, and the time is 5 hours; the coating temperature is 36°C, and the coating time is 3.5 hours.

[0075] Performance Testing

[0076] Encapsulation efficiency and drug loading: The encapsulation efficiency is 88% and the drug loading is 20%.

[0077] Targeting efficiency: Under an external magnetic field of 0.2T, the targeting efficiency is 85%.

[0078] Antioxidant properties: Antioxidant activity increased by 55%.

[0079] pH responsiveness: At a pH of 5.5, the drug release rate was 20% per hour; at a pH of 7.5, the release rate was 4% per hour.

[0080] Enzyme responsiveness: In the presence of β-glucuronidase, drug release increased by 45% after 5 hours.

[0081] Example 3

[0082] Raw material preparation

[0083] Florfenicol derivative: florfenicol 9g, 2-mercaptobenzothiazole 7.8g, DCC 11g, DMAP 0.7g, and appropriate amount of dichloromethane.

[0084] New biodegradable polymer carrier: PLGA-PEG-PLGA, the molar ratio of lactic acid to glycolic acid in the PLGA segment is 75:25, the number average molecular weight of the PEG segment is 2000Da, 22g.

[0085] Smart targeting microspheres: same as in Example 1.

[0086] Antioxidant synergists: Ferulic acid 1.5g, Vitamin C 2.5g, EGCG 1g.

[0087] pH responsive coating material: PDMAEMA-MMA 8g.

[0088] Enzyme-responsive nanogel: same as Example 1.

[0089] Preparation process

[0090] The method is basically the same as Example 1, except that: the reaction temperature for the synthesis of florfenicol derivatives is 22°C, and the reaction time is 15 hours; the stirring speed for the preparation of drug-loaded microspheres is 650 r / min, the temperature is 26°C, and the time is 4 hours; the coating temperature is 32°C, and the coating time is 2.5 hours.

[0091] Performance Testing

[0092] Encapsulation efficiency and drug loading: The encapsulation efficiency was 78% and the drug loading was 15%.

[0093] Targeting efficiency: Under an external magnetic field of 0.2T, the targeting efficiency is 75%.

[0094] Antioxidant properties: Antioxidant activity increased by 45%.

[0095] pH responsiveness: At a pH of 5.5, the drug release rate was 15% per hour; at a pH of 7.5, the release rate was 2% per hour.

[0096] Enzyme responsiveness: In the presence of β-glucuronidase, drug release increased by 35% after 7 hours.

[0097] Comparative Example

[0098] Raw material preparation: ordinary florfenicol preparation, without adding smart targeting microspheres, antioxidant enhancers, pH-responsive coating materials and enzyme-responsive nanogels.

[0099] Performance Testing

[0100] Experimental data showed that the three new florfenicol formulations significantly outperformed traditional formulations across key performance indicators. In terms of encapsulation efficiency, Example 2 achieved the highest value of 88%, while Examples 1 and 3 achieved 82% and 78%, respectively, while the comparative examples failed to achieve effective encapsulation at all. In drug loading tests, Example 2 performed the best at 20%, while Examples 1 and 3 achieved 18% and 15%, respectively. Traditional formulations also failed to achieve measurable effective drug loading.

[0101] In targeting tests, under a 0.2T magnetic field, Example 2 demonstrated the highest targeting efficiency of 85%, while Examples 1 and 3 achieved 80% and 75%, respectively. The control sample exhibited no targeting at all. Regarding antioxidant performance, Example 2 achieved a significant 55% improvement, while Examples 1 and 3 achieved increases of 50% and 45%, respectively.

[0102] pH-responsive release testing showed that at pH 5.5, a simulated gastric acid environment, Example 2 achieved the fastest release rate, reaching 20% per hour, while Examples 1 and 3 achieved 18% and 15% per hour, respectively. At intestinal pH 7.5, all Examples achieved sustained release, with the release rate dropping to 2-4% per hour. In enzyme-responsive testing, Example 2 achieved the best performance, with a 45% increase in release within 5 hours. Examples 1 and 3 achieved 40% and 35% increases in release within 6 and 7 hours, respectively. Conventional formulations exhibited no enzyme-responsive properties.

[0103] The comprehensive performance comparison of the embodiment and the comparative example is shown in the following table:

[0104]

[0105]

[0106] Table 1

[0107] Conclusion: This table comprehensively compares the examples and comparative examples across multiple key performance indicators. It clearly demonstrates that the patented florfenicol derivative long-acting sustained-release formulations offer significant advantages in terms of encapsulation, drug loading, targeting, antioxidant properties, and responsive release, while the comparative examples underperform in these areas or even lack relevant functionality, fully demonstrating the innovation and effectiveness of the patented formulations.

[0108] The comparison of the remaining amount of the example and the comparative example at different time points is shown in the following table:

[0109] Time (days) Example 1 Example 2 Example 3 Comparative Example 0 100％ 100％ 100％ 100％ 5 70％ 75％ 65％ 30％ 10 50％ 55％ 45％ 10％ 15 30％ 35％ 25％ 2％

[0110] Table 2

[0111] Conclusion: This table shows the remaining drug levels at different time points for the Examples and Comparative Examples. The remaining drug levels in the Examples were significantly higher than in the Comparative Examples, indicating that the patented formulation possesses a long-lasting sustained-release property, maintaining drug concentration for an extended period of time. In contrast, the rapid release and degradation of the drug in the Comparative Examples makes it difficult to achieve a long-term therapeutic effect.

[0112] While embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions, and variations may be made to these embodiments without departing from the principles and spirit of the invention, and that the scope of the invention is defined by the appended claims and their equivalents.

Claims

1. A long-acting sustained-release preparation of a florfenicol derivative, characterized in that: The invention is composed of a florfenicol derivative, a novel biodegradable polymer carrier, intelligent targeting microspheres, an antioxidant synergist, a pH-responsive coating material, and an enzyme-responsive nanogel; the florfenicol derivative is formed by linking florfenicol and 2-mercaptobenzothiazole via an amide bond, and the reaction process is as follows: The novel biodegradable polymer carrier is a poly(lactic acid-glycolic acid)-polyethylene glycol-poly(lactic acid-glycolic acid) triblock copolymer, wherein the molar ratio of lactic acid to glycolic acid in the poly(lactic acid-glycolic acid) segment is 75-85:15-25, and the number average molecular weight of the polyethylene glycol segment is 2000-3000 Da, accounting for 18%-28% by weight; The smart targeting microspheres are made of magnetic nanoparticles Fe3O4 wrapped with polydopamine, which is then modified with the targeting ligand folic acid, accounting for 4%-7% by mass; the antioxidant enhancer is a complex of ferulic acid, vitamin C and epigallocatechin gallate, accounting for 3%-6% by mass; the pH-responsive coating material is dimethylaminoethyl methacrylate-methyl methacrylate copolymer, accounting for 6%-12% by mass; the enzyme-responsive nanogel is composed of poly N-isopropylacrylamide-acrylamide-methacrylic acid and a β-glucuronidase-responsive linker, accounting for 5%-10% by mass.

2. The long-acting sustained-release preparation of florfenicol derivative according to claim 1, characterized in that: The encapsulation rate of florfenicol derivatives in the new biodegradable polymer carrier reaches 75%-90%, and the drug loading capacity is 12%-22%; by controlling the preparation temperature at 28-32°C, the stirring speed at 600-900r / min, and the ultrasonic power at 80-120W, the encapsulation rate and drug loading capacity can be precisely controlled.

3. The long-acting sustained-release preparation of florfenicol derivative according to claim 1, characterized in that The magnetic nanoparticles Fe3O4 in the intelligent targeting microspheres have a particle size of 15-25nm, a polydopamine layer thickness of 30-40nm, and a folic acid modification amount of 0.2-0.4mg per milligram of microspheres; when the external magnetic field strength is 0.1-0.3T, the microspheres can quickly target the lesion site, and the targeting efficiency is improved by 30%-50%.

4. The long-acting sustained-release preparation of florfenicol derivative according to claim 1, characterized in that: The mass ratio of ferulic acid, vitamin C and EGCG in the antioxidant synergist is 1.5-2.5:2.5-3.5:1-2; the complex can increase the antioxidant activity of the preparation by 40%-60% and significantly reduce the oxidative degradation of florfenicol derivatives.

5. The long-acting sustained-release preparation of florfenicol derivative according to claim 1, characterized in that: The glass transition temperature of the pH-responsive coating material is 32-38°C. At a pH of 5-6, the coating swells and the drug release rate is 12%-22% per hour. At a pH of 7-8, the release rate is 2%-6% per hour.

6. The long-acting sustained-release preparation of florfenicol derivative according to claim 1, characterized in that: In the presence of β-glucuronidase, the enzyme-responsive nanogel responds within 3-6 hours, destroys the gel structure, accelerates drug release, and increases the release amount by 30%-50%.

7. The preparation process of the long-acting sustained-release preparation of florfenicol derivative according to claim 1, characterized in that: The following steps are involved: Synthesis of Florfenicol Derivatives: Florfenicol and 2-mercaptobenzothiazole are reacted in dichloromethane at 22-28°C for 15-20 hours in the presence of a condensing agent, N,N'-dicyclohexylcarbodiimide, and a catalyst, 4-dimethylaminopyridine. The product is filtered, washed, and dried to obtain the product. The structure of the N,N'-dicyclohexylcarbodiimide is: The structure of the 4-dimethylaminopyridine is: Preparation of novel biodegradable polymer carrier solution: PLGA-PEG-PLGA was dissolved in acetone to prepare a solution with a mass fraction of 6%-9%; Preparation of intelligent targeting microspheres: Fe3O4 was prepared by chemical coprecipitation, PDA was coated by self-polymerization, and FA was covalently linked to prepare microspheres; Preparation of drug-loaded microspheres: Florfenicol derivatives and smart targeted microspheres were added to the carrier solution and prepared by the emulsification-solvent evaporation method at a stirring speed of 650-850 r / min, a temperature of 26-32°C, and a time of 4-5 hours; Preparation of pH-responsive coating material solution: PDMAEMA-MMA is dissolved in ethanol to prepare a solution with a mass fraction of 4%-7%; Preparation of enzyme-responsive nanogels: N-isopropylacrylamide, acrylamide, and methacrylic acid are used as monomers, a β-glucuronidase-responsive linker is added, and the reaction is carried out at 55-65°C for 3-5 hours under the action of an initiator; Preparation molding: Fluidized bed coating of drug-loaded microspheres, followed by coating with pH-responsive coating material and enzyme-responsive nanogel, coating temperature 32-36°C, each coating time 2.5-3.5 hours.

8. The preparation process according to claim 7, characterized in that: When synthesizing the florfenicol derivatives, the molar ratio of florfenicol to 2-mercaptobenzothiazole is (1.1-1.3):1, the amount of DCC used is 1.2-1.4 times the molar amount of florfenicol, and the amount of DMAP used is 0.06-0.09 times the molar amount of florfenicol.

9. The preparation process according to claim 7, characterized in that: In the preparation of drug-loaded microspheres, the mass ratio of florfenicol derivatives, intelligent targeting microspheres, and new biodegradable polymer carriers is 1.5-2.5:0.8-1.5:

10.

10. Use of the long-acting sustained-release preparation of florfenicol derivatives according to claim 1 in preparing drugs for treating bacterial diseases in animals, characterized in that: This preparation can achieve long-acting sustained release, targeted delivery and enzyme-triggered precise drug release of florfenicol derivatives, increasing the drug concentration in the lesion site by 50%-80%, significantly enhancing the therapeutic effect, reducing drug dosage by 30%-50%, and reducing toxic side effects.

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